Aseptic Manufacturing & Sterile Fill-Finish
WHAT IS ASEPTIC MANUFACTURING?
Aseptic Manufacturing and Sterile Fill-Finish is a process where a drug product, container, and closure are sterilized. Next, the sterilized products are moved to a cleanroom to combine the products. Self-contained equipment is typically used during this process.
INTRODUCTION TO PARENTERAL DRUGS
Parenteral drug administration is a non-oral drug or substance administered to your body internally. While there are many methods of routes, parenteral administration is done through injection (needle) bypassing the skin and mucous membranes. Sites for parenteral administration by injection include:
- Subcutaneous (SC - under the skin)
- Intramuscular (IM - in a muscle)
- Intravenous (IV - in a vein)
- Intrathecal (IT - around the spinal cord)
The intravenous administration of parenteral administration is highly effective. Therefore, it is important to make sure the container, (vial or syringe) it comes in provides excellent stability to support the pharmaceutical efficacy of these often highly expensive drugs.
These products use an Aseptic Manufacturing / Sterile Fill-Finish methodology to improve the bioavailability of the drug. Due to the complex nature, and limited resources, it is common in the pharmaceutical industry to partner with a CDMO to assist with sterile fill-finish development & manufacturing.
Types of Sterile Processing
Because injectable drug delivery bypasses the body’s natural filters that protect against bacteria and viruses, this delivery means requires drugs to be terminally sterilized or produced using an aseptic process.
Terminal sterilization is conducted after a drug has been manufacturing and uses heat, radiation, and/or filtration, but this is not always feasible and can have a detrimental effect on the product and its container. As formulations become more complex, a growing number of drug products cannot be terminally sterilized and are less effective when exposed to heat or radiation.
When terminal sterilization cannot be done, an aseptic manufacturing process is the preferred method.
Aseptic Fill-Finish is a process in which the drug product, container, and container closure are first sterilized separately and then brought together. The step of combining the product, container and closure is done in a clean room and often uses special equipment that is self-contained in a sterile environment. The aseptic fill-finish process is challenging and complex.
Due to complex production, and limited resources, it is common throughout the pharmaceutical industry to partner with a CDMO. CDMO's assist with sterile fill-finish development & manufacturing.
- Vial - A vial is a small glass or plastic vessel or bottle, that stores medication as liquids, powders or capsules. They can also be used as scientific sample vessels; for instance, in autosampler devices in analytical chromatography.
- Syringe - A vial is a small glass or plastic vessel or bottle, that stores medication as liquids, powders or capsules. They can also be used as scientific sample vessels; for instance, in autosampler devices in analytical chromatography.
- Cartridge - Cartridge syringes are intended for multiple uses, and are often sold in kits containing a pre-filled drug cartridge with a needle inserted into the piston syringe. Syringes may also have anti-needlestick features, as well as positive stops that prevent accidental pullouts.
- Vaccine - A vaccine is a biological preparation that provides active acquired immunity to a particular infectious disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins.
- Sterile - Sterile compounded medications are intended to be used as injections, infusions, or applications to the eye. Non-sterile medications include the production of solutions, suspensions, ointments, creams, powders, suppositories, capsules, and tablets.
- Injectable - An injectable drug method introduces a drug into the bloodstream…
Biologics – I would reword the second sentence to: Biologics can be composed of living entities such as cells and tissues or sugars, proteins, nucleic acids or a combination of these substances.
- Parenteral - Parenteral drugs refer to drugs using non-oral means of administration by injecting the drug directly into the body typically through three common routes of administration: intramuscular, subcutaneous and intravenous.
- Biologics - Biological products include vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or maybe living entities such as cells and tissues. Biologics are isolated from a variety of natural sources - human, animal, or microorganism - and may be produced by biotechnology methods and other cutting-edge technologies.
ASEPTIC DEVELOPMENT &
Sterile Fill-Finish Management Teams
The manufacturing process will include teams such as:
- R&D Formulation/Process Development
- Quality Assurance
- Commercial Manufacturing
- Clinical Trial Manufacturing
- Manufacturing Science and Technology (MS&T)
- Regulatory Affairs
- Analytical R&D
- Project Management
- Tech Transfer
Working with a trustworthy team throughout the development, tech transfer, and/or commercialization of Aseptic and Sterile Fill-Finish Drug Manufacturing is crucial for the product's approval, commercial success, and most importantly the impact on patient's life.
Complex Sterile Fill-Finish Development
When developing and manufacturing complex aseptic drugs, the risks are significant. However, risks can be greatly mitigated by the following:
- Preventing cross-contamination - Cross-contamination is the adulteration of a starting material, intermediate or finished product with another starting material or product.
- Employing single-use technology - Single-use bags are specially designed to mix, hold, and store batches before and after filtration. The material used to manufacture the bags poses no risk related to extractables and leachables.
- Using non-destructive testing procedures
Sterile Fill-Finish Commercial Production
Sometimes we tend to delink drug development from production, but the purpose for development is commercial production that delivers therapies to patients. Most testing and development has predictive outcomes —determining how the formulation will behave when produced in larger quantities, but it is not perfect. Agility can help sustain the momentum of the drug development process when unexpected challenges arise.
The outcomes desired by pharmaceutical development require stability and reliability, any disruption to the process is costly and can place the drug product and patients at risk. Add in the complexity and inherent risks associated with aseptic processes, operational practices that deliver agility, stability, and reliability can be the difference between failure and success.
ASEPTIC TECH TRANSFER
What is Tech Transfer?
When selecting a CDMO to partner with, there are key elements & capabilities you should look for:
- Understanding Your Product
- Manufacturing Process
- Control Strategy
- Approach to Process Validation
- Bridge to Ongoing Continuous Improvement
Vaccine Tech Transfer Process
Performing a tech transfer on a vaccine requires special attention and requires a specific skillset. Learn more about the Vaccine Tech Transfer process.
The risk to both product and process is significant in sterile fill-finish operations. It requires a high attention to detail by operations with expertise and experience with sterile fill-finish operations.
CLINICAL TRIAL MANUFACTURING (CTM)
Clinical trial manufacturing (CTM) for parenteral drugs is intended to produce batches that will be used to specifically support a clinical trial.
CTM can also mean clinical trial material(s) and is sometimes referred to as clinical trial supply (CTS). CTM is also used to refer to clinical trial management, the people or organizations conducting the trial, often a clinical research organization (CRO).
CTM projects inherently contain many variables, must be synchronized with the start of a clinical study, and have specific packaging and labeling requirements, in addition to all the other standard cGMP manufacturing requirements. Any delays or an inability on the part of the manufacturer of clinical trial supply can be detrimental to the successful outcome of a clinical trial.
When you are beginning clinical trials, it is important to develop and supply injectable products (IV, IM, and SC) and formulations including:
- Aqueous, Nonaqueous, and Highly Viscous
- Inclusion Complexes
- Dispersed Systems
- Suspensions (Aqueous and Nonaqueous)
- Polymeric Particles
Project management should be formally educated and certified. They often receive ongoing professional development that immerses them in the latest best practices that will be applied to client projects.
Project manager's are formally educated and certified and they receive on-going professional development immersing them in the latest best practices that will be applied to client projects.
Project managers are assigned for the lifecycle of the project and serve as agents for the client with full transparency. It is important for the project manager to fully understand the client's programs and their desired outcomes.
Project Manager Responsibilities
Project Managers are responsible for:
- Project Continuity
- Serves as the Client’s Agent
- Facilitates Collaboration Across Functional Areas
- Maintains a Strategic View while Working to Help Advance Daily Outcomes
- Adapts the CDMO’s Communications for the Client’s Needs
- Has the Trust of the CDMO’s Senior Leadership to Work for the Client
A great project manager will have the visibility of a senior decision-maker; anticipate FDA needs, supply chain, technology challenges, and plan accordingly for success.
ANALYTICAL R&D FOR ASEPTIC PRODUCTS
Every Aseptic Fill-Finish program begins with with Analytical Research & Development (AR&D).
AR&D groups are responsible for development and validation of the analytical methods. Analytical methods are intendent to establish the identity, purity, physical characteristics, and potency of drugs.
Timely access to accurate analytical information is fundamental for formulation development work. Extensive interactions between analytical and formulation scientists are necessary to ensure analytical methods address specific needs of each development project.
Another objective of AR&D group is to develop methods that are robust and reproducible enough to be transferred to Quality Control (QC) laboratories. AR&D teams are counted upon to lead these transitional activities and guide QC teams in the process. Given the variety and complexity of today’s drug therapies and delivery systems, AR&D scientific teams must be able to perform method development for a range of Aseptic Fill-Finish projects, such lyophilized products in vials, cartridges, and prefilled syringes.
What is Lyophilization?
Lyophilization is a freeze-drying process that removes water from a pharmaceutical product after it is frozen. This is done by placing the product under a vacuum to remove air and excess water. Typically, bulk drug ingredients that are not stable in liquid or frozen forms require lyophilization.
Products that undergo lyophilization can include:
Benefits of Lyophilized Products:
- Longer Shelf Life
- Easier Transportation of Product
- Product Stored at Room Temperature
- Safety of Product to the Consumer
- Enhancing the Stability of a Dry Powder
- Dissolution of Reconstituted Product
TYPES OF ASEPTIC CONTAINER SYSTEMS
Choosing the correct container is crucial for the stability of the drug and the safety of the patient. Types of container systems include: RTS (Ready to Sterilize) or RTU (Ready to Use also known as pre-sterilized).
Some examples of vials, pre-filled syringes, and cartridges used during the aseptic manufacturing process include:
- Borosilicate Glass for its excellent barrier properties, chemical resistance, regulatory acceptance, and a broad range of applications served.
- Polymeric materials such as cyclic olefin copolymer (COC). This combines glass and COC for greater formability, break resistance, lightweight, glass-like transparency, strong barrier, and chemical compatibility. These systems are ideal for high-value, complex molecules.
- Crystal Zenith® CZ system
- A hybrid material consisting of a molded, engineered polymer and an inert glass-like barrier coating system. The inert glass-like barrier is chemically resistant, contaminant-free, and consistent surface irrespective of the container geometry or materials of construction.
- Si02® system
STERILE FILL-FINISH LINES
When beginning an aseptic manufacturing or sterile fill-finish, a drug product will have many different needs. Some formulations, such as small-batch formulations, offer unique challenges. When speaking with a CDMO make sure that you run through the full depth of their machine offerings and capabilities.
AST GENiSYS® R
- Most Versatile Fill-Finish Line for Small Batch Production
- Automated Line Minimizes Human Intervention with Drug - Reduces Cross-Contamination
- Fill Vials, Syringes, and Cartridges - Up to 10K per day or 15-20 Per Minute
- Vials 2mL - 30mL
- Syringes 0.5mL - 5mL
- Cartridges 0.5mL - 5mL
- Equipped with:
- 2-Head Filler
- Peristaltic & Rotary Piston Pump
- Inert Gassing Capable
- Can Fill up to 40 Vials Per Minute
- Capable of Filling 3mL-100mL Vial
- Up to 500-liter Batch Size
- Equipped with:
- 2-head filler
- Rotary Piston Pump
- Inert Gassing Capable
- Can Fill up to 40K Syringes per Day or 2,400 per Hour
- Capable of Filling 0.5mL-10mL Syringes
Bosch FWR 4020
- 8-Head Filler
- Rolling Diaphragm Pump
- Inert Gassing Capable
- Can Fill up to 200K vials per day or 200 per minute
- Capable of filling 2mL-100mL
- Up to 1,000-liter batch size
cGMP Millrock® Lyophilizer
- Supports Vial Sizes Between 3ml and 50ml
- Supports Batch Sizes up to 20,000 vials.
- 60 square feet
- 8 shelves
- 24 trays
- 3600X50cc vials to 20,500X3cc vials
- Ready to Use (RTU) Sterility
- Inert Gassing Capability
ROBOTIC STERILE FILL-FINISH
When producing a drug through the aseptic manufacturing process, it is essential that aseptic technique is followed to cGMP standards. The pharmaceutical industry is evolving to reduce the risks of cross-contamination and consistently deliver sterility assurance.
Fully automated, state of the art, fill-finish suites like the AST GENiSYS(R) R, reduces risks associated with operator engagement. Additionally, automated lines provide other benefits including:
Specifically, when working with oxygen-sensitive products, the use of a robotic parenteral fill-finish machine can greatly improve, and even eliminate, the oxygen exposure.
REGULATORY & cGMP PROCESS
When looking to produce an Aseptic or Sterile Fill-Finish parenteral product, it is crucial to follow the cGMP guidelines provided by the FDA. Whether you are producing the drug yourself, or more likely, partnering with a cGMP Certified CDMO - it is important to be aware of the guidelines.
When looking at the cGMP Requirements for your drug development, the best resource is the entity reviewing cGMP practices. The FDA keeps its current regulations and practices updated on its website.
What is cGMP in the Pharmaceutical Industry?
cGMP stands for the Current Good Manufacturing Process. The United States FDA sets the cGMP standards and enforces the regulations. cGMP also provides guidelines for a variety of systems to assure proper design, monitoring, and control of pharmaceutical manufacturing processes and facilities. By following the cGMP regulations, patients can be assured that the identity, strength, quality, and purity of drug products have been properly produced by a CDMO or manufacturer.
When producing Aseptic or Sterile-Fill Finish, some key items to be aware of include:
- Making sure your clean area is properly separated and classified
- Air is properly filtered & circulated
- Personnel are properly trained, dressed, and monitored
- Containers/closures are properly sterilized and maintained
- Time limits (ex: bulk processing, sterilization, or filtration) are strictly created and followed upon
- Process has been simulated & recorded
What is PDA (Parenteral Drug Association)?
PDA stands for the Parenteral Drug Association. PDA’s mission is "Connecting People Science and Regulation®". Since its founding in 1997, the PDA formed the PDA Foundation for Pharmaceutical Education, Training and Research (PDAF). PDAF's mission includes:
- Support the education, training and research activities of the Parenteral Drug Association, Inc.
- Support education, training and research in the pharmaceutical sciences
- Increase awareness and educate the public on pharmaceutical sciences
What is ISPE (International Society for Pharmaceutical Engineering)?
ISPE stands for the International Society for Pharmaceutical Engineering. ISPE serves its members by leading pharmaceutical engineering, technical, and regulatory advancement.
ISPE is the global industry leader in connecting pharmaceutical knowledge to deliver manufacturing and supply chain innovation, operational excellence and regulatory insights to enhance industry efforts to develop, manufacture and reliably deliver quality medicines to patients.
Resources & Aseptic FAQ
There are many questions and concerns when beginning the Aseptic Manufacturing and/or Sterile Fill-Finish process. Some items can be addressed by looking at your respective governing bodies' drug approval process.
Following, or exceeding, the most up-to-date standards for Aseptic Manufacturing & Sterile Fill-Finish is crucial for product approval. Some of the most useful resources include:
Meet an Aseptic Expert
When clients with aseptic pharmaceutical projects reach out to Pharmaceutics International (Pii) for development support, they typically meet Bryan Braxton, and soon after, they get the feeling of confidence that comes with choosing the right contract developer.
The first thing one notices about Bryan is his friendly, grounded demeanor, something for which he gives credit to his parents and his blue-collar, Midwestern upbringing. Underneath that friendliness is a scientific mind that creates solutions for our most complex aseptic development projects. But how did these two traits combine in the same person?
When describing his role, he says, “it is all about relationships” and understanding the dosage form objectives of the drug sponsor. As a senior director of Aseptic R&D in a CDMO, the relationship with the drug sponsor is critically important. However, when engaged in the hard work of R&D, the important relationship is that between the science and the patient.