Best Practices for Highly Potent API (HPAPI ... - Lonza...At Visp, Lonza has a full breadth of HPAPI development and manufacturing assets, including facilities for early-phase activities,

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Best Practices for Highly Potent API (HPAPI) Development and Manufacturing

An Executive Summary

A discussion on the development, rapid scaling, and commercial production of HPAPIs, as well as integrated containment requirements for particle engineering and drug product.

OverviewDrug product development for highly potent APIs (HPAPIs) can be challenging. Complications with the interface between operations in drug substance and drug product handling can result in increased program complexity and cost. Best practices are presented here for the development, rapid scaling, and commercial production of HPAPI drug substance, along with examples of specific innovative practices that have been proven to be advantageous.

Requirements for HPAPI ProductionIn today’s pharmaceutical industry, the trend is toward more complex and more potent API molecules, with smaller companies driving innovation. At the same time, there is a shift on the drug product side toward medicines requiring the application of specialized formu-lation technology to enhance bioavailability such as micronization, spray drying, and other techniques. Additionally, because of the nature of some diseases, regulatory authorities are supporting accelerated approval mechanisms. The resulting accelerated development time-lines pose a huge challenge to any company working on highly potent products.

The increasing demand for HPAPIs is concen-trated among three therapeutic areas: oncology, antidiabetic, and autoimmune diseases, which combined, represent ~80% of the total HPAPI disease areas (Figure 1). Drug products for these diseases tend to require specialized formulation technologies such as powder-in-capsule, spray drying, or particle size reduction; two-thirds of HPAPIs in the pipeline need some level of enhancement, be it solubility enhancement, par-ticle engineering, and/or specialized delivery. For highly potent products, all of these techniques, along with the drug product fill/finish, must be performed under containment.

Philipp Künti Head of Chemical

Manufacturing Small Scale Lonza

Maurits Janssen, PhD Senior Director, Head of

Commercial Development Lonza Pharma & Biotech

S P E C I A L S P O N S O R E D S E C T I O N

BEST PRACTICES FOR HIGHLY POTENT API (HPAPI) DEVELOPMENT AND MANUFACTURING

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Production of Highly Potent APIs and Drug Products at LonzaLonza has been active in highly potent product manu-facturing for 20 years. At its Center of Excellence in Visp, Switzerland, Lonza works on highly potent products throughout the design–development–commercial manu-facturing continuum. Their capabilities include specialized HPAPI development and manufacturing, spray drying and particle-size reduction under containment, and fill/finish for low-dose/HPAPI applications. For HPAPI development and manufacture, a full chemical toolbox is available, along with biotechnology, enzyme technology, and antibody–conjugate capabilities. The plant is set up as a multipurpose plant, which means that the cleaning, decontamination, and containment is extremely critical, and the infrastructure includes processes for handling and disposal of highly potent hazardous waste. The site has been inspected by several health authorities (Figure 2). At Visp, Lonza has a full breadth of HPAPI development and manufacturing assets, including facilities for early-phase activities, upscale and process optimization, and commercial manufacturing. Using these assets, Lonza can produce HPAPI from a 1-L scale up to a 10,000-L scale (Figure 3).

To enable effective partnering and collaboration with its customers, Lonza has developed a transparent communica-tion model that promotes direct contact between the dif-ferent disciplines. For each project, Lonza appoints a project manager (PM), who coordinates all of the different disciplines, and clients work with a team of internal experts (and external experts as needed) to support all of the disciplines needed in relation to the specific project (Figure 4).

How to Increase Operational Excellence and Reduce Time to MarketTo increase operational excellence and reduce time to market, several risk-based strategies must be developed and effective procedures must be implemented that will ensure the manu-facturing process is a safe, fast, and robust. The containment strategy is a critical element that must be integrated into the risk analysis process, as well as into the technology transfer (TT) processes, both from external sources into the facility and among internal assets. Unit operations must be well aligned with predefined primary and secondary contain-ment strategies. This can be achieved by performing a gap analysis for each project, then by implementing any identified solutions and measures for the specific project. Also critical

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The demand for highly potent API (HPAPI)

• Oncology is increasingly driving global sales, accelerated approvals and the growing number of HPAPI candidates in the pipeline • Our analysis indicates that more than 55% of NME’s require some form of specialized handling (e.g. isolaHon) • Our analysis also indicates 2/3 of pipeline need some level of ‘enhancement’ in terms of solubility, parHcleengineering and/or specialized delivery

Oncology DiabeHcs & Autoimmune

dominate the HPAPI Landscape

4

Figure 1: Demand for highly potent API.

Figure 2: Lonza Center of Excellence for API / HPAPI Development and Manufacturing at Visp, Switzerland.

Regulatory Authorities: U.S. FDA, Agência Nacional de Vigilância Sanitaria,Cofepris, Health Canada, KFDA, Swissmedic, T.C. Sağlık Bakanlığı.



are the establishment of effective cleaning procedures, the determination of acceptance criteria, the establishment of a clearly-defined start-up sequence for production, and proven standard decontamination procedures (Figure 5).

With respect to containment, it is important to focus on primary containment, sampling containment during and at the completion of individual manufacturing steps, cleaning processes, and waste management. Proven systems must be available for supporting containment throughout the entire manufacturing process. Consideration should be given to flexible, isolated systems that can cover a wide range in the quantity of seed crystals/starting material. Also, because HPAPIs have a very low Occupational Exposure Limit (OEL), effective sampling containment and representative sampling techniques must be established. For example, an endless liner system may be used when unloading material from a

dryer or centrifuge. Containment also must be available in the Quality Control laboratory. In addition, cleaning procedures must focus on the low contamination level and difficult-to-clean areas. Equipment must remain closed until clearance of rinse samples to ensure adherence to OELs. Closed rinsing of reactor charging pipes needs to be performed without removal of valves. Off-gas systems also must be cleaned with direct connection to the HPAPI system to collect cleaning solvents. Finally, effective and efficient waste management procedures are needed, including segregated waste streams for different highly potent compounds. This may include liquid, solid, and gaseous waste (Figure 6).

While it is highly critical to have an effective strategy for primary containment systems and technical infrastructure, at least 50% of the operational performance will be related to the workforce. Therefore, for faster operational excellence,

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Significant features of HPAPI development & manufacturing

PM

Sales

ProducHon

Sourcing

Controlling

MSAT/ Development

LogisHc

QC

QA

Eng

Others

Strong program management

Technology transfer acHviHes

Link of SHE assessment and established procedures vs. project specific requirements

Waste management

Interfaces to producHon

People

Compliance- and inspecHon track record

Figure 3: Overview of Lonza HPAPI assets at Visp, Switzerland.

Figure 4: Significant features of HPAPI development and manufacturing at Lonza.



management must drive proper behaviors by establishing and communicating Key Performance Indicators (KPIs) for safety, quality, and job performance, and by maintaining a high-level commitment to safety and quality, through compliance and on-the-job training.

Go-Digital Material Management for HPAPIThrough the implementation of go-digital material manage-ment for HPAPI, Lonza has demonstrated how the application of digitalization and automation helps cope with increasing containment requirements. In this case, it was possible to reduce the overall workload by 5%, as well as to reduce the overall change over time.

Four elements that are important in this case are safety, innovative investments, efficiency in dealing with occupa-tional hygiene requirements, and data integrity. Constantly monitoring and improving occupational hygiene is a pre-requisite for highly potent API manufacturing and ensuring safety. New investments must be innovative and create over-proportional value. Efficiency in occupational hygiene can be improved by reducing the overall workload related to material handling. Data integrity can be assured by routinely assessing the data integrity performance of 21 CFR Part 11 validated electronic systems.

The concepts applied in the case study are illustrated in Figure 7. In the previous HPAPI material flow process, as shown on the left side of the figure, two operators are required for every batch. The working operator, working in the secondary containment environment, adds the raw materials to the reactor, while a second operator, working outside of the containment environment, is overseeing the actions of the working operator, checking results, performing calculations, and monitoring the clearance of the starting materials.

In the new arrangement, as shown on the right side of the

figure, the execution of the process is documented in the Management Execution System (MES). There is a centralized area where the portions are created, then the different por-tions are transferred to the reactors. One operator can charge the reactor, while the MES is used to check the identity, quality, and quantity of the raw materials being charged.

HPAPI MonoplantAs a means of ensuring operational excellence and reducing time to market, Lonza has built a monoplant (i.e., dedicated plant) to produce a single product for a full year for one customer. Because the facility is dedicated entirely to a single product, minimal cleaning effort is needed and the disadvantages of having to perform product changeovers are avoided. In addition, several activities can be automated

“Through the implementation of go-digital

material management for HPAPI, Lonza

has demonstrated how the application

of digitalization and automation helps

cope with increasing containment re-

quirements. In this case, it was possible

to reduce the overall workload by 5%,

as well as to reduce the overall change

over time.”


Increase operational excellence and reduce time to market by working with strong procedures

ContainmentstrategyasintegratedpartofriskanalysisandTTprocessAligned unit operaHons with defined primary and secondary containment. Execute gap analysis on this concept and define project specific measure if required only

CleaningprocedurePre-, Mech.-, Main cleaning with clear acceptance criteria for open equipment aner pre-cleaning

Equipmentstart-upsequenceStandard process embedded into risk assessment

process contains leak test and rinse prior to producHon. Defined acceptance criteria's for

producHon release

Provenstandarddecontamina@onprocedures

Top down approach requirements with bopom up evaluated procedure.

10

Safe, fast and robust process

implementaHon

Figure 5: Increase operational excellence and reduce time to market with strong procedures.



and real-time analytics can be implemented. Using th is approach, the cost of goods was r e d u c e d by a l m o s t 50%. Also, by keeping critical buffers in stock at a l l t imes, and by ensur ing product ion capacity is available at all times, rapid customer response is possible r e g a r d l e s s o f a n y fluctuation in demand. O v e r a l l c u s t o m e r r e s po nse t im e wa s significantly improved; the lead time from order to delivery was reduced from 24–36 months to six weeks (Figure 8)

Bioavailability Optimization Capabilities at LonzaM a n y H PA P I s a r e n o t h i g h l y s o l u b l e ; therefore, drug product bioavailability often is an issue and particle size reduction is needed. To address this, Lonza has facilities with capabilities related to particle engi-neering in Quakertown, Pennsylvania; Monteggio, Switzerland; and Bend, OR. I n these f ac i l i -ties, which have been inspected by several regulatory authorities, var ious technologies are in place for particle size reduction: milling, micronization and spray d r y i n g f o r H PA P I s , cytotoxic compounds, and highly sensitizing c o m p o u n d s . Lo n z a has worked at these facilities on thousands of compounds requiring bioavailability or particle size optimization.


Proven systems available supporting primary containment of entire process

Focus on primary containment as success driver for HPAPI manufacturing

Solid charging

containment

Aligned unit operaHons with defined primary- and

secondary containment

Different systems for wide quanHty range 50g seed crystals to 200kg starHng

material

Gap analysis instead of starHng from scratch

Define project specific measurement




Sampling Containment

Sampling of reactor soluHon/suspension over

loop system

Sampling for drying determinaHon check with

liner system

Liner port to lock-in & lock-out glass sampling boples




Unloading Unloading out of dryer and

centrifuges with endless liner system

Release sample taken as “small porHon” during unloading. Containment for further

dispensing in QC lab available

Unloading and sampling out of filter dryer over flex isolator and

endless liner




cleaning processes

Closed equipment unHl clearance of rinse sample is key to ensure occupaHonal

hygiene limits

Equipment for closed centrifuge basket cleaning in “difficult to clean” areas

Closed rinse of reactor charging pipes w/o further

removal of valve

Cleaning of off-gas system with solvent and direct

connecHon to HPAPI waste system

Figure 6: Focus on primary containment as success driver for HPAPI manufacturing.



Another capability Lonza has applied to HPAPIs with limited solubility is customized development and manufac-ture of lipid- or liquid-based drug products, at its facilities in Edinburgh, UK and in Ploermel, France. Several types of cus-tomized highly potent formulations can be produced at these facilities, including lipid-based formulation, liquid-filled hard capsule, soft gel, API-in-capsule, and micro-dose formulation. Specialized technology is available for the following: controlled substances, colonic delivery, capsule-in-capsule technology, abuse-deterrence, hormones, and enTRinsic™ Drug Delivery Technology. Lonza also has capabilities involving traditional hard capsules at their Tampa, FL, facility. These facilities have been inspected by various regulatory authorities.

ConclusionDrug product development for HPAPIs can be complex and costly. To address the increasing demand for highly potent products, Lonza has developed dedicated highly potent drug product manufacturing facilities at Visp, Switzerland, and they have established several other facilities dedicated to customized development and manufacture. At these facilities, Lonza has instituted effective best practices for development, scale-up, and containment; applies innovative technologies to improve operational excellence and reduce time to market; and has specialized capabilities involving enhancement techniques that can be used to overcome bioavailability and solubility limitations that are common with HPAPIs.


Increasing containment for HPAPIs & implement go-digital material management

Bulk Material

PorHons for one Batch

DocumentaHon / Release

Project 1

Project n

Project 1

MES

Project n

Pervious NEW

MES

M

ES

Increase containment level support data integrity aspects debopleneck batch processes

implement efficiency by digitalizaHon

Batch 1 2 3 4 n Batch 1 2 3 4 n

Operational leverage to cope with increasing containment requirements by digitalization and automation

18


Key benefits for the customer

Case study – HPAPI monoplant

COSTOFGOODSCOGS reducHon by 50% compared to iniHal campaigns

RAPIDRESPONSEIntermediate “buffer stock” management: rapid response to demand fluctuaHon

SECURITYOFSUPPLYGuaranteed capacity access for criHcal

manufacturing steps every year

FLEXIBILITYLead Hme from order to delivery reduced from

more than 24-36 month down to 6 weeks

VALUE

Figure 7: Increasing containment for HPAPIs and implementation of go-digital material management.

Figure 8: HPAPI monoplant.


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Best Practices for Highly Potent API (HPAPI ... - Lonza...At Visp, Lonza has a full breadth of HPAPI development and manufacturing assets, including facilities for early-phase activities,