Lyophilization: Optimizing

Production

Common Process Problems and

Inefficiencies

• Across any industry using lyophilization, the process is

often developed with insufficient empirical product data

• Product lyophilization cycles are not optimized for process

equipment and materials used

• Consequently, clients encounter issues with:

– Product reproducibility

– Formulation

– Inconsistent dryness across batches

– Cycle duration and procedures

– Breakage of vials and containers

– Overlong cycles cost more to run and reduce

throughput

– Poorly dried product will exhibit shorter shelf life and

Consequences of Poorly Defined Processes and Products:

– Poorly dried product will exhibit shorter shelf life and

reduced activity

– A lack of data about product and process will create

problems for quality control and regulatory

submissions

Characterization

• To develop a reliable, successful freeze drying cycle, the critical

performance parameters of the formulation must be understood. BTL

quantifies and assess them, to maximize your product and process

quality and performance.

• Case study: A customer had a protein formulation in phase I, and • Case study: A customer had a protein formulation in phase I, and

requested its analysis and the recording of critical temperatures.

These enabled the client to develop a cycle which delivered freeze

dried product with good rehydration and stability.

• Advantages:

• Financial: Devise a cost effective process

• Operation: Feasibility of candidate formulation

• Regulatory: Safe and reproducible cycle

Quantitative Product

Characterization

• Using a combination of DTA and Impedance

analyses, BTL’s Lyotherm 2 instrument enables

identification of endothermic and exothermic identification of endothermic and exothermic

events and molecular mobility in a frozen product.

It uses:

– Differential Thermal Analysis (DTA) to determine

thermal events

– Impedance to identify structural events

• Freeze-drying microscopy (FDM) allows the study

of freeze-drying at microscopic level

• Lyostat 3, developed by BTL, is effectively a micro

Quantitative Product

Characterization

• Lyostat 3, developed by BTL, is effectively a micro

freeze dryer where a small sample can be

observed throughout the process

• The process of crystallization and the effects of

annealing can also be studied

• The quantitative information obtained includes:

– Eutectic temperature for a crystalline material

– Collapse temperature for an amorphous material,

– Tg’(Glass transition): the temperature at which a frozen amorphous system will change from the ‘glassy’ state

Quantitative Product

Characterization

– Tg’(Glass transition): the temperature at which a frozen amorphous system will change from the ‘glassy’ state to a more ‘rubbery’ state (which typically precedes to collapse)

– Teu (Eutectic temperature): the temperature at which a frozen crystalline solution will melt (a discrete temperature)

– Tm (Melting point): This is the melting temperature of the frozen solvent

Consulting and R&D services

• We provide expertise in 5 core service areas:

– Characterization;

– Formulation Development;

– Cycle Development; – Cycle Development;

– Scale-Up and Optimization;

– Troubleshooting

Formulation Development

• BTL has significant expertise in the formulation of products,

accounting for the lyophilization steps involved in the development

and/or production process. Acting at an early stage minimizes issues

otherwise encountered later in scale-up and downstream processing.

• Case Study: BTL was requested to characterize a formulation• Case Study: BTL was requested to characterize a formulation

developed by a client which contained a problematic buffer system. A

low collapse temperature was identified as well as pH shift on

freezing, requiring a new formulation to be developed.

• Advantages:

• Financial: Formulation of a product that aligns with the most cost

effective lyophilisation process

• Operational: Robust, time-efficient procedure

• Regulatory: Detailed product data mitigates risks

Cycle Development

• Whether in the pharmaceutical and biologics R&D sector, the generics

drugs or commodities market, reformulation of a product is not always

an option. BTL provides the expertise to identify the best route

forward for making the most of your lyophilization cycles.

• Case Study: A customer had a 70 hour cycle which was limiting the• Case Study: A customer had a 70 hour cycle which was limiting the

manufacturing capability at the site. Through analysis of the product’s

thermal characteristics BTL was able to decrease the drying time by

40%.

• Advantages:

• Financial: decrease cycle duration and/or adjusting the critical

temperature to reduce energy costs

• Operational: Decreased batch turnaround time

• Regulatory: Easily validated

Scale-Up and Optimization

• BTL supports clients on all aspects of freeze-drying along the pipeline

of development phases. This applies to any industry, with particular

benefit to the Pharma/Biotech sector.

• BTL’s strategy when developing a cycle is to account for the technical

specifications of the production dryer that will be used at productionspecifications of the production dryer that will be used at production

scale.

• Case Study: BTL supported the customer from cycle development to a

full scale manufacturing process, assisting the technology transfer.

• Advantages.

• Financial: An effective lyophilization cycle in terms of temperature,

and duration, keeping energy costs low.

• Operational: Efficient and scalable procedure.

• Regulatory: Reproducible and well characterized.

Troubleshooting

• In depth practice in supporting clients experiencing unexpected

problems. We generally advise engagement with cycle development

and formulation early in the R&D steps. However, we are ideally

positioned to address issues occurring at any stage, allowing you to

continue your activities while we focus on their resolution.

• Case Study: A customer had product at Phase III, which began to

demonstrate collapse in a number of vials. BTL revisited the freeze-

drying cycle and formulation, adapted the duration of the primary

cycle, and this resolved the problem.

• Advantages:

• Financial: Mitigate any loss due to interruptions

• Operational: Experts will quickly address issues encountered

• Regulatory: Rapid return to validated process and product

• Characterization: Typically 1 to 2 weeks, but for urgent

requirements, arrangements can be made for execution within a

day.

• Formulation Development: From 1 to 4 weeks, depending on

number of formulations and required customer testing.

Typical Timelines*

number of formulations and required customer testing.

• Cycle Development: From 4 to 8 weeks.

• Process Scale-up and Optimisation: 2 to 10 weeks.

• Troubleshooting: Up to 6 weeks.

*Dependant on client requirements.

Training courses

• Since 1997, we have run more than 120 training

courses in freeze-drying

• We have trained more than 2,500 people

• 2-day courses focus on Product and Process• 2-day courses focus on Product and Process

• 3-day courses cover Product, Process, Equipment

Design & Qualification

• We also offer tailored, on-site courses

BTL’s own R&D projects

• Freeze-drying of red blood cells

• Freeze-drying of collagen implants for knee repair

surgery

• Freeze-drying of probiotic bacteria• Freeze-drying of probiotic bacteria

• Freeze-drying and polymorphism to increase

herbicide efficiency

• Freeze-drying of fusion proteins as intelligent

insecticides

Laboratories & Facilities:

Analysis

• Lyotherm 2: DTA and Impedance analysis

• Lyostat 3: Freeze-drying microscopy

• mDSC: modulated Differential Scanning Calorimetry

• Karl Fischer Titration: moisture analysis• Karl Fischer Titration: moisture analysis

• FMS: Frequency Modulation Spectroscopy

• Through BTL’s collborations with world-class universities and

specialist organisations, we can also offer analysis such as SEM,

total surface area analysis, DVS (dynamic vapour sorption), XRD

(x-ray diffraction).

Laboratories & Facilities:

Production

• 3x VirTis Genesis freeze dryers: offers 4 shelves, with processing capacity range from

• 1mL product (in 2mL vial) over 4 shelves = 1824 vials (1.824 L )

• to 20ml (in 50mL vial) over 4 shelves = 165 vials (3.3 L)

• Small production scale

• 1x VirTis Ultra freeze dryer: offers 10 shelves, with processing capacity range from

• 1mL product in 2mL vials, over 10 shelves = 4560 vials (4.56 L)

• 20mL product in 50mL vials, over 10 shelves = 412 vials (8.25 L)

• Or, bulk trays can offer 3L per shelf, yielding:• Genesis: 12L (4 trays)

• Ultra: 30L (10 trays)

Value of BTL Consulting

services to you

“The strengths of our unique scientific team and our

unparalleled experience in freeze-drying gives us

the ability to help our customers achieve their

goals, maximising their financial, operational and goals, maximising their financial, operational and

regulatory positioning”

Contact us: btl@biopharma.co.ukVisit us: btl-solutions.net