Research & Development
For over 20 years, Doppel R&D Department has gained expertise in developing numerous pharmaceutical formulations of Finished Drug Forms (FDF).
From the early formulation stages to the validation and industrialisation process, Doppel R&D Department applies its competence to improve drug efficacy through the development of advanced pharmaceutical formulation.
By providing their skills throughout the entire new-drug approval process, Doppel R&D Department can support clinical and BE studies and manage technical files and specific documentation until the Drug Product application is submitted to Regulatory Autorities.
Doppel Pharma CDMO R&D Department consists of, dynamic, highly specialised scientific staff comprised of 26 people:
8 FTEs (7 scientists and 1 unit head)
12 FTEs (9 scientists and 3 technicians)
Pre-clinical and clinical staff
3 FTEs (1 scientist, 1 technician, and 1 unit head)
3 FTEs (1 QA manager, 1 GMP compliance manager, and 1 QP)
Standard technologies include:
- Sterile ampoules
- Soft gels
- Solid Oral Dosage Forms (tablets; sachets; capsules)
- Semisolids (creams; suppositories)
- Liquids (drops; drinkable vials; syrups)
Mini-tablets: more than a pellet, less than a tablet
Mini-tablets are a small-sized dosage form (2 to 3 mm), yet they ensure the same robustness and easy-to-manufacture process as a tablet.
Mini-tablets allow greater accuracy in dosing and greater flexibility in therapy.
Higher patient compliance, especially for paediatric patients, as they easily disperse in water, milk, or juice.
The same tablet technologies can be applied: immediate-release, delayed-release, and functional coating (pH and non-pH-dependent).
Mini-tablets can be packaged in multiple bottles, multiple dispensers, single-dose sachets, or combined with another drug product (powder, granules, etc.) in hard-soft gel capsules for combination therapy.
Multi-layer tablets: combination therapy for greater patient compliance
An innovative tableting machine allows the manufacturing of tablets comprised of up to 3 different layers.
Each tableting machine is fitted with a pneumatic aspirator to prevent contamination of the single monolayer.
With integrated and robust control of the compressive forces during manufacturing, the process guarantees the homogeneous content and dosage of the individual single layers.
Multi-layer tablets allow:
- The combination of two or more drug substances, even when chemically or physically incompatible.
- Greater patient compliance, especially with combination therapy and for elderly patients, as the risk of forgetting drug doses is reduced.
- The combination of multiple drug release profiles: immediate and prolonged release of the same or different drug substances can be combined to improve compliance.
- Our skill and experience in coating (functional or aesthetic film coating) multi-layer tablets to modify release or improve appearance.
Modified release/Specific site delivery: a localised and controlled therapy for greater efficacy and fewer side effects
The objective of oral administration is to control the release of the therapeutic agent and thus control drug absorption by the gastrointestinal tract.
This may include delayed-release (e.g., enteric-coated), extended-release (ER), and orally disintegrating tablets (ODT).
The benefits of these types of formulations include:
- Sustained blood levels
Therapeutic blood-level concentrations can be maintained over extended periods with once-daily administration.
- Attenuation of adverse effects
These formulations prevent high, peak blood concentrations from being attained soon after administration, as occurs with conventional dosage forms. Consequently, adverse effects from transiently high concentrations can be avoided.
- Greater convenience and patient compliance
Short half-life drugs must often be administered at frequent intervals throughout the day (at least twice daily) to maintain blood concentrations within the desired therapeutic range. These extended-release products offer the potential reduction of daily doses (to once a day), can improve patient compliance, and help prevent missed doses.
- Protecting acid-sensitive drugs
With delayed-release drugs, an enteric coating is usually used to protect the product until it has passed through the gastric bladder and reached the gut. The aim is to protect acid-sensitive drugs from gastric acid, thus reducing stomach irritation.
Doppel R&D Department has vast experience in modified-release development, such as:
- Functional coating (pH-dependent and independent)
- Erodible or swallowable matrixes
- Multi-layer tablets having different kinetic-release properties
- Multiple systems (hard granule-filled capsules, mini-tablets, pellets, or both)
Doppel R&D Department and DPL Pharma (a subsidiary of Doppel) developed and patented a new drug delivery platform: T-Chrono Platform Technology.
This platform is a modified controlled-release solid oral pharmaceutical composition that includes a core containing one or more active ingredients, as well as an outer coating of the core, with the following features:
- The core consists of:
- a complex monolithic matrix containing an active ingredient, or
- a complex monolithic matrix adjacent to an immediate-release layer containing the same active ingredient that is contained in the monolithic matrix.
- The coating is made up of a layer consisting of pH-dependent and/or pH-independent polymers.
This new platform was applied to three different therapeutic areas:
- The gastrointestinal area
- The anti-diabetic area
- The cardiovascular area
and 4 patents were filed in 2018.
In each therapeutic area, the aim was to ensure the drug substance can be delivered to a specific site of the body (e.g., the gastrointestinal tract) and drug availability matches the course and progression of the disease so that therapeutic outcomes can be improved and side effects minimised.
Doppel R&D Department has a 950-sqm plant in Rozzano dedicated to GMP Research and Development.
This GMP area includes:
- The clinical and pilot-batch pharmaceutical development and manufacturing area
- The primary packaging and clinical labelling/kit assembling area.
- The analytical development, validation methodologies, and ICH stability area.
The GMP area features innovative technologies and provides a full service, from pre-formulation activities to pilot and validation batch manufacturing and clinical supply.
Our service includes:
- Physicochemical characterisation of substances
- Drug development and process scale-up thanks to flexible equipment
- A wide range of manufacturing technologies thanks to a wide variety of equipment and features
- Pilot and validation batch manufacturing
- Analytical development and validation
- ICH stability of the drug product
- Clinical supply with customised packaging design
We offer our scientific experience in developing and analysing a wide range of drug products, such as tablets (including mini-tablets, multi-layer tablets, coated tablets), semisolid products, liquids and suspensions, and capsules (filled with multiple products such as powders, granules, mini-tablets, or pellets, liquids and capsules for blind clinical studies).
Early Stage development area
In 2020, Doppel Farmaceutici expanded its R&D capabilities with a new area dedicated to the early stages of development that provides:
- Customisable and flexible systems that expedite formulation and process development
- Innovative and adaptable equipment for small batch sizes
- Faster development timelines
- The production of smaller batches using less active substance
- The immediate commencement of the project
- A quick analysis of development trials
- The same expert scientific staff for GMP and non-GMP development
- More trials, less time, and lower costs
- The mirroring of Doppel Farmaceutici’s pilot and production capabilities
- GMP experience applied in the development field: the same accuracy but fewer “rules” for a non-GMP area
High potency oral: end-to-end R&D to marketing
The demand for high potency drug product manufacturing has steadily increased over the years, and the trend is expected to continue. Our pharmaceutical R&D department focuses on developing increasingly specialised drugs, resulting in increasingly potent APIs.
Doppel Farmaceutici and its R&D department offer their experience with a wide range of products and technologies, including developing and manufacturing high-potency drug products.
As a partner specialised in high potency drug products, we can provide:
- Specialised operators working on high-potency substances
- Dedicated areas (weighing rooms, manufacturing rooms, and primary packaging)
- Handling procedures and safety controls
- A close collaboration between R&D scientists and production, resulting in an end-to-end connection from drug-product development to the commercial side: implementing an efficient, outstanding strategy at the outset and creating a strong foundation for scaling up manufacturing.
Our clinical staff have vast experience in pre-clinical and clinical supply and can therefore offer:
- Customised packaging design, including blinding solutions (blisters, bottles, sachets, vials, tubes, etc.)
- Label design, printing and application
- Flexible and accurate labelling services:
- Single and multi-lingual
- Plain and booklet labels
- Randomised and open study
- Variable text
- Sequentially numbered
- Barcode printing
- Code-break envelopes
- Patient-kit assembly
- Collaboration with CROs and universities for Phase I to Phase III clinical trials
- An in-house thermal transfer printing that satisfies 21 CFR and Annex 13 requirements
- Customised supply-chain logistics with a qualified courier
With increasing frequency, R&D scientists have focused on the development and clinical supply of paediatric formulations. Doppel R&D department has frequently been involved in developing and supplying paediatric formulations dedicated to orphan diseases.
Most of the skill-intensive technologies used in the R&D department can be applied to paediatric oral administration, especially for easily manipulated and multi-dose systems.
Available paediatric technologies include:
- oral solutions and suspensions
- orally disintegrating tablets, dispersible tablets, scored tablets, mini-tablets
- formulations requiring manipulation such as sprinkle capsules, powder for oral solution, powder for oral suspension, granules for oral suspension, oral powders and granules.
Furthermore, encouraging preservative-free pediatric formulations has resulted in fewer multiuse solutions or suspensions in favour of single-use solid oral dosage forms.
R&D Doppel has vast experience in developing paediatric mini-tablets (from 2.5 mm):
- These are a small-dosage form (2 to 3 mm) yet ensure the same robustness and easy-to-manufacture process as a tablet without using preservatives.
- They can be easily dispersed in water, milk, or juice, improving compliance.
- Minitablets can be packaged in multiple bottles, multiple dispensers, or single-dose sachets.
- Mini-tablets allow greater accuracy and flexibility in therapeutic dosing, especially for paediatric patients whose dosage must often be adjusted based on weight.
In the last 5 years, Doppel R&D Department enhanced its experience in orphan drug development, as well as in NDA and IMPD submissions.
In 2019, Doppel Farmaceutici obtained US FDA approval without form 483 for an orphan drug capsule. The drug product was developed by R&D as the generic version of a marketed specialty drug and was transferred to commercial manufacturing for the market.
The developed product demonstrated benefits compared to the reference product in terms of stability and storage conditions.
Doppel R&D Department offers its knowledge and experience with orphan drugs for:
- Smart development with the best optimisation possible for a larger number of trials and less API
- Technology to adapt the different dosage strengths to patient compliance and acceptance
- Flexible equipment for small batch sizes
- The purchase of excipients from certified suppliers according to customers’ requirements
- Chemical and microbiological testing of raw materials according to current pharmacopoeias (EuroPharma, USP, etc.)
- The development and evaluation of analytical methods
- Pilot-scale production required for product development and stability testing
- Consolidated experience in NDA submission
- Stability studies, considering the climatic conditions of the customer’s market (Stability Zones)
- Detailed production records for each batch made available to the customer upon request
- Competitive lead times and immediate response to extra orders
- Flexible and on-time deliveries
Established in 1994, Doppel is today recognized as one of Europe’s leading experts in contract R&D and manufacturing. It has start-of-the-art facilities and highest scientific capabilities to service its international pharmaceutical and nutritional clients.