Services Provided by The Zlota Company

The key differentiator in the services that we provide is our capability to contribute to both the process chemistry and the chemical engineering aspects of a project, while understanding complex business objectives and organizational dynamics.

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We Provide Project Support and Training in the Following Areas:

Risk Analysis

As part of our project support, in the area of Risk Analysis, The Zlota Co. provides clients with the following:

Recommendations for the formation of a suitable team to conduct risk analysis, avoiding the selection of too large or too small groups, with possible background bias.
Guidance for building an effective cause-and-effect diagram, in particular to avoid possible confusion ensuring the inclusion of meaningful process parameters during the brainstorming stage.
Advice in defining ranking scales for semi-quantitative risk assessment, to be consistently used by the team*.
A semi-quantitative method for risk analysis suitable for the project stage: one method for early, and another for late development, or for prior to technology transfer to a plant
- For early development projects we enable rapid risk analysis, avoiding “busy work”, and spending too much time for such analysis, producing short, manageable documents summarizing the risk assessment.
Advising in designing effective pre-DoE (statistical design of experiments) as one-variable-at-a-time (OVAT) experiments, using the fundamental science available, an important factor in determining the success of a DoE.

*Ranking scales, together with other general recommendations for a particular company are often captured in an internal guideline for QbD implementation, a suitably short document, updated as needed, which we help compile. Such internal guidelines lead to recommendations for best practices for QbD implementation in that specific organization.

For additional information please contact us.

Statistical Design of Experiments (DoE), Design Space, Risk Quantification

As part of our project support, in the area of DoE, The Zlota Co. provides clients with the following:

Guidance in the selection of a suitable group of factors to be included in a screening DoE, most importantly for the definition of the factor ranges to be used*.
A check-list for DoE execution necessary to ensure that the data generated is suitable for statistical analysis.
Advice regarding the inclusion of scale-independent and scale-dependent factors.
Recommendations for the design of a screening DoE matrix suitable for the generation of the necessary process understanding using the resources available to the team.
Clarify the best options for a DoE in early versus late development projects.
Reconcile, as needed, the recommendations of a sponsor and those of a CRO.
Guidance about the use of appropriate DoE software, for both the design as well as for the data analysis and interpretation, balancing statistical with practical significance.
Advice for the use of the screening DoE results for the design, as appropriate, of an optimization (Response Surface Methodology, RSM) DoE.
Using available (target) specifications, support for meaningful identification of “sweet spots”, and possible Design Spaces.
Using risk calculations, guidance for meaningful proposal of a Design Space, of Potential Critical Process Parameters, and of appropriate verification experiments.
Ensure that all DoE reports, in particular those used to support a proposed Design Space, are written in full compliance with the QbD ICH guidelines, as well as with those of various regional regulatory agencies.
Guidance with the scale-up of the Design Space.

* Such guidance, together with other general recommendations for a particular company are often captured in an internal guideline for QbD implementation, a suitably short document, updated as needed, which we help compile. Such internal guidelines lead to recommendations for best practices for QbD implementation in that specific organization.

For additional information please contact us.

Chemical Process Scale-Up

As part of our project support, in the area of chemical process scale-up, The Zlota Co. provides clients with the following:

Guidance for the design of scale-up and/or scale-down investigations, for chemical reactions, API crystallizations and micronization processes*.
Advice with the design of experiments aimed at identification of scale-up factors, for homogeneous as well as for heterogeneous chemical processes (solid-liquid, liquid-liquid, and gas-liquid systems).
Clarification of the assessment of the controlling mixing mechanism in the process at stake: micromixing, mesomixing, macromixing, or a combination thereof.
Recommendations for the use of suitable lab equipment for the execution of scale-up investigations, as well as for the effective use of Process Analytical Technology (PAT) tools aimed at developing suitable process understanding in the minimum number of experiments.
Recommendations for the use of appropriate scale-up factors as DoE variables.
Guidance for the building of an equipment database using suitable mixing and scale-up calculations, including guidance with the use of appropriate software for such calculations.
Advice with the selection of suitable plant equipment (reactor, agitator) for technology transfer and scale-up, in particular for cases of multipurpose equipment, including recommended operating conditions based on the results of the scale-up investigations conducted.
Guidance for suitable scale-up strategies for drug product process scale-up, using a meaningful blend of scale-up science and of statistical design of experiments (DoE).

* Such guidance, together with other general recommendations for a particular company are often captured in an internal guideline for QbD implementation, a suitably brief document, updated as needed, which we help compile. Such internal guidelines lead to recommendations for best practices for QbD implementation in that specific organization.

For additional information please contact us.

Additional Areas Supported

API Crystallization Process Development and Scale-Up
Micronization Process Development and Scale-Up
Process Analytical Technology (PAT)
Design Space definition, verification, and process risk quantification
Non-critical, Key and Critical Process Parameters definitions

Effective partnerships between sponsors and Contract Research Organizations
QbD section of a Chemistry, Manufacturing and Control section of a regulatory filing
QbD ICH guidelines: ICH Q8, Q9, Q10, Q11, Q12, Q13 and Q14; the FDA Emerging Technology Program and the Quality Metrics Guideline

For additional information please contact us.

Courses Offered by The Zlota Company

NEW Course: Crystallization and micronization scale-up for improved API processability

Introductory concepts

Processability of API bulk powder
Risk analysis
Practical approaches to processability model development

Crystallization process scale-up

Highlights of crystallization process development
Practical approaches to crystallization process scale-up
Downstream operations

Micronization process scale-up

Highlights of micronization process development
Practical approaches to micronization process scale-up

API bulk powder physical properties of interest and their measurement

Particle size and shape
Rheology
Electrostatic properties
Flowability

Data Analysis

Big data analysis
Machine Learning analysis
Principal Component Analysis (PCA) for unstructured data
Case studies

Hands-on workshops

Crystallization scale-up example
Micronization scale-up example
Machine Learning analysis example
Principal Component Analysis example

NEW Reaction Development Using Statistical Design of Experiments (DoE)

Introductory concepts

Review of key DoE concepts
DoE feasibility

Case Study #1

Early development DoE
Pre-DoE experimentation
Challenges with categorical factors
Meaningful numerical factor ranges
Design discussion
Fit-for-purpose data analysis
Machine Learning tool
Statistical vs. practical significance
Chemical knowledge vs. statistical analysis
Follow-up DoEs

Case Study #2

DoE for reaction and work-up
Responses
Design Discussion
Replication, blocking
Fit-for-purpose data analysis

Case Study #3

Design Augmentation strategies
Design quality
Scale-independent and scale-dependent factors
Design discussion
Fit-for-purpose data analysis

Case Study #4

Optimization (RSM) designs
Meaningful PAT use
Design discussion
Fit-for-purpose data analysis
Model editing strategies
Verification experiments

Case Study #5

Process Robustness
Design discussion
Fit-for-purpose data analysis
Probabilistic risk calculations
Design Space, PARs/NORs
Critical Process Parameters
Visualization tools
Technology transfer
Principal Component Analysis for historical batch data analysis

Practical Approaches to Statistical Design of Experiments (DoE) for the Design of Robust Chemical Processes

Topics discussed in the course:*

Introduction
DoE fundamentals :
- Pre-DoE, factor types, ranges, levels
- Scale independent and scale dependent factors
- Responses
- Randomization, centerpoints, blocking

Screening the Experimental Space: design options
Screening the Experimental Space: data analysis (statistical vs. practical significance)
Optimization (Response Surface Methodology, RSM) designs, and data analysis
DoE for QbD:
1. Design Space proposal, verification
2. Critical Process Parameters
3. Process risk calculations
4. Process robustness quantification
5. Process validation

Special designs
Hands-on workshops, DoE software familiarization
Review

* On-site courses are customized to the needs of the client. A course for Drug Product formulations is delivered in-house as well (which includes mixture, and mixture-process designs).

For additional information please contact us.

Practical Approaches to Chemical Process Scale-Up

Topics discussed in the course:*

Introduction
Scale-up challenges
Scale-up theory, types of similarity
Mixing mechanisms
Mixing calculations for chemical process scale-up; the value of an equipment database
Fast homogeneous reactive systems scale-up
Heterogeneous process scale-up (solid-liquid, liquid-liquid, gas-liquid)
Mixing effects on heat transfer
Special topics
Hands-on workshops, mixing and scale-up software familiarization
Review

* On-site courses are customized to the needs of the client. A course for Formulation Process Scale-up is delivered in-house as well.

For additional information please contact us.

Robust Crystallization Process Development and Scale-Up Using QbD Tools

Topics discussed in the course*:

Introduction
Risk analysis for Crystallization Process Development
Product understanding (Crystallized API)
Desupersaturation methods
Statistical Design of Experiments (DoE) for Crystallization Process Development
Crystallization process scale-up
Process Analytical Technology (PAT) for Crystallization Process Development
Downstream processing (including micronization process scale-up overview)
Questions and Answers, Round Table Discussion

* On-site courses are customized to the needs of the client. A course for Drug Product formulations is delivered in-house as well (which includes mixture, and mixture-process designs).

For additional information please contact us.

Services Provided by The Zlota Company

We Provide Project Support and Training in the Following Areas:

Courses Offered by The Zlota Company

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