Roadmap for Drug Product Development and Manufacturing of Biologics.pptx

Roadmap for Drug Product
Development and Manufacturing of
Biologics
Department of Pharmaceutics
B. K. Mody Government Pharmacy College,
Rajkot
Prepared by – Chintan S Kalsariya
M.pharm- Pharmaceutics
Semester - II

INDEX
No Title
1 Introduction
2 Define roadmap
3 Pre-Clinical/ Phase-I Development
4 Phase II Development
5 Phase III development
6 PPQ/Commercial
7 Conclusion

1. Introduction
 The development of therapeutic biologics involves a
streamlined approach for their formulation and drug product
development from early stages to process validation and
commercialization.
 This roadmap is based on experience with approved products
and aims to improve safety, efficacy, and immunogenicity
profiles in human patients, as well as maintain consistently high
quality, efficiency, and reduced cost.
 The approach should be applicable across all biotherapeutic
products.

1. Defining the road map for drug product
development
Biopharmaceutical development focuses on quality products
and processes for patient needs. Challenges are addressed
through a roadmap based on Quality by Design principles.
Early clinical studies use a platform approach, while novel
modalities require more extensive studies. As development
progresses, further studies are conducted to maintain quality
and stability.
Close collaboration between teams is crucial to understand
process modifications affecting product quality and stability.

2. Pre-Clinical/Phase-I Development

The early stage of development for a biological
drug product includes several key activities with
the goal of submitting an Investigational New
Drug (IND) application to regulatory authorities
and gaining approval to initiate Phase I clinical
trials
These activities are part of a larger drug product
development roadmap, which is discussed in
subsequent sections.

A. Initial QTPP Development
QTPP (Quality Target Product Profile) in the
pharmaceutical industry is important for:
1. Defining drug product quality characteristics.
2. Focusing on CMC (Chemistry, Manufacturing, and
Controls) attributes. including intended use, dosage form,
delivery system, dosage strength(s), formulation, storage
conditions, container closure system, and drug product
quality criteria.

3. Assisting in selecting the modality and final candidate molecule in early
development.
4. Incorporating anticipated commercially important product characteristics.
5. Acting as a communication tool between industry and regulatory agencies.
6. Establishing characteristics for enabling the clinical trial program.
7. Promoting dialog between product development and clinical teams.
8. Being a living document updated with new knowledge from development and
trials.

 Common issues during development for different biologics
DP presentations.
Liquid formulation Lyophilized formulations Pre-Filled Syringes
related issues
Formulation and excipient
related issues
related issues
related issues
Instabilities of the
molecule :example -
protein
Instabilities of the
molecule
Components of PFS that
can induce instability
Container closure an
device-related issues
Lyophilization (process)
related issues
Issues related to PFS
functionality
Issues related to
application to the patient

Timeline and material for biologics drug product development, characterization and
qualification studies.

B. Analytical Development
To develop analytical assays for defining the degradation and impurity profile of the
drug product, the following steps are typically taken.
a. Product-specific assays
These are developed for API and focus on product quality, activity, and potency.
Examples include:
 Size exclusion-high-performance liquid chromatography (SE-HPLC) for protein
aggregates.
 Analytical ultracentrifugation for empty and full AAV capsids.

 Capillary electrophoresis sodium dodecyle sulfate (CE-SDS) protein aggregates
 Isoelectric focusing (IEF) for change hetrogenicity related to post translational
modification.
 Binding assay for establishing early activity and functional assay for potency.
b. Analytical platforms
Companies develop analytical platforms for molecular entities, allowing for
evaluation of new products using established analytical assays.
Examples include:
- SE-HPLC, Reduced and non reduced CE-SDS and cIEF

c. Non Product specific assay
These aim at product quality and are typically compendial assays established by
pharmacopeias such as the United States Pharmacopeia, European Pharmacopeia, and
others.
Examples include:
 pH, osmolality, protein concentration, container closure integrity, sterility, bacterial
endotoxin, and extractable volume.
 Color, clarity, visible particulates, sub-visible particulates, For some molecules,
product-specific analytical methods can also be found in pharmacopeias (e.g.,
RP-HPLC for insulin, polysorbate).

C. Formulation Development :
1. Selection of excipients, raw materials, and consumables:
o GRAS (Generally recognizes as safe) directory, FDA inactive ingredient guide,
and UCSF Excipients Browser use for excipient selection.
o Consider sourcing appropriate grade materials for later manufacturing.
2. Characterization of the molecular entity:
o Understand impurity profiles, including PTMs (post translation modification),
aggregates, and process residuals.
o Monitor stability, particle formation, and immunogenic potential.

3. Platform formulations for early-phase development:
o Typical liquid platform formulation for mAbs: 25-100 mg/mL mAb, histidine buffer,
polysorbate 80, and isotonic sucrose at pH 6-7.
o Advantages include speed to the clinical and verification of stability through a
minimal set of studies.
4. Storage considerations:
o Platform liquid formulations at 2-8 °C storage, or lyophilized formulations to avoid
PTMs during storage.
5. Antibody-drug conjugates (ADCs) and cell/gene therapy formulations:
o Consider the stability profiles of the antibody and linker drug DS materials separately
and as a final DP material.
o Minimize heterogeneity to prevent increased aggregates and loss or hyperactivity of
the molecule.

6. Particle characterization:
o Use orthogonal techniques like flow imaging and background membrane imaging
to understand particle profiles and root causes.
7. Compatibility with the storage container:
o Use pre-defined container/closure systems to ensure compatibility, reduce
manufacturing costs, and speed up development.
8. Pre-defined container/closure systems:
o Common vials are ISO-2R, 6R, and 10R glass type I with either 13mm or 20mm
fluoropolymer coated elastomeric stoppers.
o Obtain vials pre-washed and depyrogenated, and stoppers pre-washed and ready to
sterilize, mimicking the manufacturing process.

D. In-use compatibility studies
 Compatibility and stability studies with delivery systems are
necessary before clinical use.
 Industry publications provide guidance on biological product
in-use stability and compatibility. Pharmacy Manual outlines
steps for diluted DP in IV bags, types of IV bags, storage
conditions, and in-line filters
 Compatibility studies should demonstrate compatibility with
saline and/or dextrose using representative IV bag/infusion
set. Both PVC and non-PVC bags are used for IV bag
construction.

Syringe compatibility studies are necessary for stability prior
to patient delivery. IV bags should not be transported via
pneumatic tubes due to particle formation risks.
Product transport studies may be needed if the pharmacy is
separate from the clinic.
Without microbial challenge data, storage time in IV
bags/syringes is limited to 4 hours at room temperature,
varying by country/regulatory authority.
Formulation platforms can support longer IV bag hold periods
with microbial challenge studies.

D. GMP DP Manufacturing and Stability Monitoring :
 A this stage the DP should be designed so that no special process requirements are
needed to fill the DS into the primary packaging material.
 Produce formulated bulk DS directly into formulated bulk DP.
 Include a dilution step if needed for early phases.
 Typical tests include bioburden, protein concentration, filter integrity, fill
weight, appearance, sterility, and container-closure integrity.
 Toxicology batch can serve as the lead lot for Phase I, if provided no significant
changes in formulation and process.
 Leverage toxicology lot stability information to extend GMP lot shelf-life during
studies.

2. Phase-II Development :
•Phase I process and DP format can be used for Phase II studies.
•Late-stage DP development for a biologic involves multiple activities across three
phases:
a. Phase II
b. pivotal studies/Phase III
c. PPQ/Commercial launch.

 Activities in late-stage development are more labor and
material intensive due to factors like formulation
redesign for quality, potency, and safety, patient
comfort and compliance considerations, manufacturing,
distribution, and regulatory requirements.
 Studies aim to provide comprehensive data and
information for DP sections of the BLA (biologics
license application)

1. QTPP ( Quality target product profile) and Analytical Methods :
 Commercial DP is introduced during of the pivotal Phase III clinical trial. the
initiation
 QTPP requirements need alignment with updated commercialization
characteristics early in Phase II.
 Patient-centered considerations, like using PFS/autoinjector for home
administration, enhance compliance and comfort.
 Development of commercial formulation and container/closure system
should begin during Phase II to allow for sufficient stability data collection.
 Include Information from similar products, Phase II study design, animal
modeling studies, and marketing team input guide formulation and
container/closure strategy.

 Coincident with defining commercial DP attributes, critical
quality attributes (CQAs) must be refined for formulation
design.
 Depending on commercial needs, certain quality attributes may
become CQAs, requiring development of new analytical
methods.
 Early assessment of potential degradation pathways (oxidation,
iso-aspartate formation, deamidation) is crucial.
 Additional assays developed for formulation studies should be
done in cooperation with analytical development teams to
ensure comparability.
 Plans should be designed to demonstrate comparability of
methods to avoid changes in stability profiles of development
and clinical lots.

2. Formulation Development :
 Formulation designed in pre-clinical/Phase I for speed, Phase II formulation for
pivotal/Phase III and commercialization.
 Stability requirements become more stringent, and patient-centric design gains
importance.
 Biologics typically require storage at 2-8°C for at least two years with
additional room temperature stability.
 This may lead to particle formation and post-translational modifications,
necessitating consideration of new surface interactions.
 Ideally, the product is in its final container closure with a delivery device like
an autoinjector. However, the dose, administration method, and delivery
device may not be known initially, requiring flexibility.

- References to reviews for proteins, mAbs, cell-based therapies, lipid nanoparticles,
and viral vector-based therapies, as well as publications on quality by design concepts,
excipients, and GMP manufacturing readiness, can aid in the formulation design.
- For Ab's, formulations may increase concentration for higher doses and use pre-filled
syringes with autoinjectors. This can drive concentrations towards 200 mg/mL and
beyond, necessitating non-standard PFS or on-body injectors. Development timelines
must account for these changes.
- Comparing Phase III/commercial formulations to those used in Phase I clinical
studies is vital to avoid changes in the stability profile and clinical safety signals.
Significant differences may necessitate a cross-over or bioequivalence clinical study
before Phase III clinical trials.

3. Additional Studies Supporting Formulation Development:
 Additional studies needed: transportation, photostability, updated in-use stability,
container/closure system, and device compatibility.
 Transportation study to simulate real shipping conditions for DP stability.
 Collaborate with experienced groups or companies for validated shipping
simulation.
 Photostability studies to assess degradation risk under expected use conditions.
 Consider additives to reduce photodegradation risk.
 Update in-use stability studies for Phase III and commercialization.
 Consider microbial challenge studies for reconstituted products.
 Decisions on additional studies should be made with clinical teams and
pharmacies.

4. Container Closure Systems :
 Evolution of primary container closure systems:
• New vial types: glass, plastic, hybrid
• Multiple pre-filled syringe (PFS) configurations: silicone
oil, baked or crosslinked silicone oil, plastic, new glass
with gore stoppers and no silicone oil
 Importance for combination products:
• Compatibility with drug product during development
• Parameters affecting quality, potency, and safety:
ejection rate, needle characteristics, device temperature,
hold time, device leachates.

 Considerations during pharmaceutical development:
• Influence on drug product (DP) stability.
• Gas permeability and container contact surface affecting
DP performance.
• Higher gas exchange rate in plastic vials leading to
oxidation.
• Hydrolytic attack and delamination of glass vials due to
formulation components.
• Product loss and leachates from staked needle syringes.

5. Initial Formulation Robustness Studies :
 Robustness studies using Design of Experiments (DoE) aim to
demonstrate the relationship between factors affecting a
process and its output.
 Conduct the full DoE study as early as possible after formulation
development, with representative Phase III process material
available.
 Define excipient and other formulation ranges prior to setting
specifications for Phase III and commercial batches.
 Manufacturing process variability due to factors like excipient
manufacturers, buffer preparation, API concentration, etc.,
should be accounted for by placing limits on important
parameters.

 Understand the limits on excipients, biologic concentration, temperature range, and
storage time, and their effects on product quality and stability using DoE.
 Use the output of analytics to provide limits on manufacturing parameters and
predict impurity limits and inherent variability expected from stability programs.
 Define product profile limits that provide for quality, potency, and safety without
forcing rejection of a lot or unduly shortening product storage stability.
 Choose a design that ensures parameters affecting product quality, potency, and safety
can be enhanced with additional parameters later in development.

The drug product manufacturing process faces various challenges including
aggregation, particle formation, oxidation, leachate impurities, bioburden problems,
sterility issues, and incomplete mixing after thawing or dilution.
Collaboration between the formulation team and the drug product manufacturer,
particularly with the increasing outsourcing to different Contract Development and
Manufacturing Organizations (CDMOs), is crucial.
Key steps to address these challenges include conducting early development studies
on platform filters, mixing, and tubing/pumping compatibility.
6. DP Process Development :

 Freeze/thaw studies at scale with placebo or protein solutions, such as bovine serum
albumin, help define thawing parameters
 Potential formulation fixes in later stages may necessitate additional clinical studies
and it can cause timeline delays.
 Collaboration with the intended drug product manufacturer is essential due to the
different equipment configurations affecting final product quality. For lyophilized
products, developing a lyophilization cycle and design space, considering scale-up and
transfer, is crucial.
 These studies, along with formulation robustness, form the basis for defining Critical
Quality Attributes (CQAs) and in-process control strategies.

 Activities focused on finalizing process, formulation, and analytical methods for
clinical study and commercial launch
 Process validation involves three stages of process validation as per FDA guidance:
Stage 1 - Process Design:
• Define commercial manufacturing process based on development and
scale-up knowledge.
3. Phase III Development :

Stage 2 - Process Qualification:
• Evaluate process design for reproducible commercial
manufacturing.
• Demonstrate reproducibility using successful batches.
Stage 3 - Continued Process Verification:
• Ensure ongoing assurance of process control during
routine production.
• Prevent process drift beyond established qualified
process range.

 Refine QTPP (for commercialization) materials
 Update TPP and QTPP based on Phase II results, revise CQAs, and refine product
label for accurate efficacy and safety data.
1. Internal Manufacturing or CDMO Site Selection :
 The selection criteria for a CDMO (Contract
Development and Manufacturing Organization) should
prioritize a facility that matches the QTPP (Quality
Target Product Profile) requirements, technical needs,
manufacturing capacity, cost of goods, quality, and
regulatory profile.

 Ideally, material for Phase III/pivotal clinical studies should be
produced at the same manufacturing site as planned for commercial
launch, considering comparability.
 Differences in unit operations between Phase I and pivotal DP (Drug
Product) manufacturing should be addressed, and additional small-
scale studies may be necessary.
 If the product requires a PFS (Patient-Filled Syringe) or other special
device, these requirements should be considered in CDMO site
selection.

2. Photostability Under ICH Guidelines and Confirmatory Use conditions :
 Photostability studies are crucial for protein-based
products to assess light-induced degradation.
 These studies follow ICH guidelines and evaluate the
product under intended use conditions.
 Final packaging design may not be ready, requiring
additional studies later.
 "Light mapping" data should be used to minimize
damage during manufacturing and distribution.

3. In-Use Compatibility Studies :
 the study needs to look at various devices like syringes, IV bags, and infusion systems
that might be used in the final product.
 It should consider the different materials these devices are made of and how they might
affect the product. The study could benefit from knowing what types of devices are
commonly used at the testing sites. This includes different types of syringes, IV bags
with or without certain chemicals, and filters.
 The study should also consider how these devices work together, like how an
ambulatory pump or on-body device might interact with the product. While this
roadmap doesn't cover all the details for on-body devices, it's important to remember
that they have their own set of requirements and tests.

3. Refine In-Process Control Strategy :
 Design and implement in-process control strategies based
on CQAs and QTPP, following regulatory guidance.
 Include measures like bioburden/endotoxin testing,
density/protein concentration measurement, filter
integrity checks, fill weight inspection, particle analysis,
etc.
 Ensure consistent quality, potency, and safety before
patient use.
 Document strategy in a technology transfer report for
large-scale batch initiation, ensuring site awareness of
requirements.

4. DP Small Scale and Engineering Run :
 The manufacturing process involves tests using small-
scale or similar materials to ensure quality standards
are met.
 The engineering batch helps set parameters for
mixing, filling, and quality checks, ensuring
consistency across different batch sizes.
 It also helps set up the freeze-drying cycle and other
parameters. Results are summarized in a report to
finalize the process outline and strategy for GMP
batches.

5. GMP DP Batch for Pivotal Clinical Studies :
 After evaluating the engineering batch, the team initiates the GMP batch with pivotal
DS material at the commercial CDMO.
 All testing follows cGMP practices, using qualified methods. It's best to validate
methods before pivotal material release to ensure consistency with PPQ material.
 If not feasible, avoid changes that may affect quality profiles. If new methods are
introduced, perform bridging studies.
 For the first two batches, review results before starting the next to refine processes and
control strategies.
 Include pivotal batch data in IND amendment for initiating pivotal studies, and
follow ICH guidelines for release and stability testing.

6. Process Risk Assessment :
 after pivotal studies, teams prepare for process characterization
and PPQ stages.
 A process risk assessment is conducted using methods like
FMEA (Failure Mode and Effects Analysis) to evaluate safety,
efficacy, and quality.
 Protein DS is combined with primary packaging for product
integrity, while stress factors are identified to assess their impact
on quality.
 FMEA helps identify process failures affecting safety, efficacy,
and quality.

 A joint assessment by manufacturing, analytical, quality, and drug product teams
identifies Critical Process Parameters (CPPs).
 Based on this, a process control strategy is developed to minimize risks, and the risk
assessment report is updated as risks are reduce or tolerated before the PPQ stage.
7. Process Characterization Studies :
 In DP manufacturing, process characterization uses pivotal or representative
material, with scale-down models if necessary.
 Characterization studies employ qualified analytical methods and investigate
parameters like pH, temperature, and mixing speed.
 Critical control parameters are identified, and studies may coincide with
formulation robustness assessments.

Results define PAR (proven acceptable range) and NOR (normal operating range),
and the process control strategy is finalized after PPQ batches.
8. Sterile Filter Validation :
Sterile filter validation is essential for pharmaceutical manufacturing.
Initiate validation when preparing for Process Performance Qualification
(PPQ).Validation may take 4 to 12 months.
Parameters include bubble point determination, physicochemical, microbiological
(including microbial challenge study), and Extractables & leachable testing.
Validated filter and process conditions define sterile filtration for PPQ batches.

9. Transportation Studies for Product Impact :
 Ideally, transportation studies are performed during
commercial formulation development to select
appropriate excipients for product protection.
 If not possible during development, studies should be
conducted using material from the pivotal process.
 Issues like inadequate surfactant levels causing
unacceptable particles may arise, leading to delays
and the need for formulation changes or
development of analytical techniques.

 Initial transportation studies involve shock, drop, truck, and air transport
simulations using representative material.
 Timely evaluation before commercialization ensures product integrity during
transportation.

4. PPQ/Commercial
1. Finalize CQAs :
 Batch release results are crucial for determining product quality and stability.
 Analyze batch release results, early development and pivotal batch stability
trends for product quality and stability.
 Use forced degradation studies and characterization of purified fractions to
assess potency and finalize CQAs.
 These studies and analyses are used to finalize the list of Critical Quality
Attributes (CQAs).

2. Commercial Manufacturing Site :
 When choosing a manufacturing site for commercial production, companies usually
prefer to use the same location as the pivotal manufacturing site.
 This helps avoid the complications of comparing processes and product quality
between different sites.
However, there may be situations where additional sites are needed to meet the
demand for the drug product (DP).
If more sites are needed, they must be qualified and show comparable quality to
the pivotal study.

3. Manufacturing Site Risk Assessment(FMEA) for Commercial Phase :
 FMEA-based risk assessment, conducted by the manufacturing site, evaluates
facilities fit, equipment qualification, and utilities to identify potential
manufacturing process risks before PPQ runs.
 allowing the CDMO (Contract Development and Manufacturing Organization) to
determine if any risk mitigation measures are necessary before proceeding with
process performance qualification (PPQ) runs.
 Updates to the risk assessment indicate whether risks have been mitigated or
tolerated during PPQ.
 Like other process documents, the manufacturing site's risk assessment is
continuously updated throughout PPQ preparation and execution.

4. Raw Material Risk Assessment :
 Excipients, raw materials, and consumables must meet pharmacopeial
standards.
 Raw materials need high purity, low extractables and leachable, and adherence
to QTPP standards.
 Before process qualification, raw material risks are assessed, and control
measures are implemented.
 Control strategies may involve second sourcing and rigorous testing.
 Addressing supply chain constraints early in PPQ strategy avoids delays.
 Raw material batches may require qualification before commercial launch.

4. Validation Plan, Activities and Process Control Strategy :
 A master validation plan outlines efforts for project stages, covering equipment,
utilities, and facility validation, among others.
 It includes activities like sterility assurance, seal integrity qualification, and
analytical assay validation.
 FDA guidance on periodic equipment qualification ensures microbial control.
 Final process control strategy is based on critical quality attributes and process
parameters.
 Components include in-process controls, release specifications, and comparability
studies.

5. Process Performance Qualification Batches :
 In simpler terms, the Process Performance Qualification (PPQ) runs are done at the
commercial manufacturing site to ensure the product is stable and meets quality
standards.
 You need to have stability data for at least three batches, and one of those batches
should be in the final packaging. The number of PPQ batches needed depends on
factors like the batch size, mixing speed, and other validation parameters.
You should also consider doing at least one PPQ batch with the final packaging to
make sure the product quality isn't affected during the packaging process.
 This batch can be used for further studies like shipping lane validation.

6. Continuous Process Verification (CPV)
 Continuous Process Verification (CPV) ensures
that the drug manufacturing process remains in
control during commercial production.
 CPV includes monitoring quality attributes and
process parameters to maintain consistency.
 Data compiled in the CPV process is included in
the annual product quality review report for
regulatory submission.

7. Preparation of BLA (biologics license application ) and Pre-Approval (PAI)
Inspection :
 Before BLA submission, teams ensure all deviations, OOS (out of specifications) ,
and OOT (out of trend) observed in clinical supply, registrational, stability, and PPQ
batches are reported to regulatory agencies and addressed scientifically.
 Preparation for BLA and PAI inspections involves data integrity checks, lab
notebooks review, traceability verification, and mock audits to ensure readiness.
 These measures ensure integrity and credibility with regulatory inspection teams,
determining the company's ready to manufacture batches that meet safety, efficacy,
and potency standards.

 Reference
 “Journal of Pharmaceutical Sciences” - Roadmap for Drug Product
Development and Manufacturing of Biologics by Krishnan Sampathkumar,
BruceA. Kerwin

Roadmap for Drug Product Development and Manufacturing of Biologics.pptx

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