Tuesday, January 17, 2012
What Is The Scorecard?
The following white paper provides a quantitative approach to assessing risk in oral drug development programs with respect to Chemistry, Manufacturing, and Controls (CMC) activities. Pharmatek’s Drug Development Risk Assessment Scorecard allows managers to get a dashboard view of critical areas in their specific drug development program. Once the components of risk are understood, strategies can be implemented to mitigate some of this risk going forward.
Pharmatek’s Drug Development Risk Assessment Scorecard defines 8 key categories where project managers can evaluate the risk associated with their project. These 8 categories, along with a brief definition, are provided below.
Category
|
Definition
|
|---|
| BCS Classification |
BCS I (soluble and permeable), II (not soluble but permeable), III (soluble but not permeable), or IV (not soluble or permeable). |
| API Supply |
Quantity and quality of research, non-GMP, and GMP batches of API. Timing of API availability is key. Considerations: form (crystal/amorphous), polymorphs? |
| API Stability |
Stability in solid state (oxygen, moisture, light, heat) and in solution (aqueous pH range). Stability-indicating analytical method required. |
| Highly Potent/Cytotoxic |
APIs characterized as highly potent or cytotoxic require special handling, limiting vendor selection and increasing development costs. Use Pharmatek, Merck, Safebridge, or other qualified banding system. |
| Dosage Strength |
Proposed dosage strength for FIM. Anything outside the range of 1mg to 250mg may require additional formulation considerations. |
| Formulation |
What is proposed FIM dosage form?: PIC, PIB, dry blend, or solubility enhancing formulation. Staged development approach vs. final formulation? |
| Quality of CMC Leadership |
Source of CMC strategies to support all development needs such as quality, timing, scientific scope, and cost. |
| Timing |
The development timeline leading to the proposed IND filing date.
|
Scoring
Each category is given a numeric score of 0, 1, or 2, based on its assessed risk to the drug development program using the following scale.
0 – Low Risk
1 – Standard Risk
2 – High Risk
The risk score for each category is summed to generate a Total Score. The Total Score is then used to quantitatively assess the Overall Project Risk for any given drug development program using the guideline below. A high risk score is not uncommon, and will benefit from the de-risking strategies provided below.
| Total Score |
Overall Project Risk |
| 0-4 |
Low |
| 5-8 |
Standard |
| 9-16 |
High |
Using The Scorecard
There is clearly a level of subjectivity involved when assigning a Risk Score for a given category. The following table summarizes two hypothetical oral drug development programs with all categories scored ‘0’ or all categories scored ‘2’ to help frame the evaluation.
Category
|
Low Risk (all scored ‘0’)
|
High Risk (all scored ‘2’)
|
|---|
| BCS Classification |
BCS Class I |
BCS Class IV |
| API Supply |
Same batch of 2kg available for non-GMP and GMP development and FIM. Impurity profile leaves room for error upon further scale up. Crystalline material with single polymorph. |
Only 200g of research batch available for development (produced in-house). Non-GMP and GMP batches made by different suppliers (offshore for non-GMP, US for GMP). GMP API available less than 1 month before CTM manufacture. |
| API Stability |
Stable at room temperature and 40°C without desiccant in clear glass bottle. Stable in aqueous solution from pH 1-9. |
API is hygroscopic and degrades when stored for 1 month at 25°C as a solid. Light sensitive. Degrades in water. |
| Highly Potent/Cytotoxic |
Not classified at HP/C. (Pharmatek Band 2, Merck Band 2, Safebridge Band 2, or below) |
Requires special handing as a HP/C compound. (Pharmatek Band 3, Merck Band 3, Safebridge Band 3, or above) |
| Dosage Strength |
All dosage strengths between 5 mg and 50 mg |
Dosage strengths below 1 mg or above 250 mg for single unit |
| Formulation |
PIC or simple dry blend in capsule |
Liposome, emulsion, amorphous dispersion, or melt granulation |
| Quality of CMC Leadership |
In-house CMC professional (or consultant), experienced with phase appropriate approach to IND process |
No CMC experience (i.e. discovery chemist or clinical background only). Only experienced in Phase 3/Commercial drug products. Consulting firm recommends work that isn’t phase appropriate. |
| Timing |
Development timeline ≥ 9 months |
Development timeline ≤ 3 months |
De-Risking a Drug Development Program
The most common approaches used to mitigate risk in a drug development program are described below, along with the corresponding Risk Categories that each action may impact. Based on over 12 years of experience as a pharmaceutical CDMO and working with 100’s of different drug candidates, it is our opinion that the most effective way to reduce the total project risk, short of altering the compound itself, is to ensure a CMC professional skilled in early phase drug development is contributing to the project. The Overall Project Risk should be considered along with many other factors for a drug development program, including the therapeutic indication.
Action
|
Risk Category
|
How Risk May Be Reduced
|
| Alter Salt Form or Physical Form of API |
BCS Classification |
Improve solubility, target BCS I |
| API Supply |
Easier synthesis, reduce impurities, reduce batch size by increasing solubility/bioavailability |
| API Stability |
Crystalline form may improve stability |
| Dosage Strength |
Improved solubility may reduce dosage strength and risk of side effects |
| Formulation |
Improved solubility may reduce time, cost, and complexity of formulation development |
| Extend Timeline |
API Supply |
Representative API available for development work, ideally the GMP batch of API intended for CTM |
| Timing |
Allow time buffer for unexpected scientific results |
| Increase Investment |
API Supply |
Make a single GMP batch for development and CTM |
| Quality of CMC Leadership |
Improve strategic direction of development program |
| Timing |
Meet objectives by performing work in parallel |
| Improve Quality of CMC Leadership |
API Supply |
Identify options to improve solubility, quality, and manufacturing of API |
| API Stability |
Identify stable polymorph or salt form |
| Dosage Strength |
Minimize dosage strength through improvements in API solubility and understanding of clinical design |
| Formulation |
Identify the most efficient approach to achieve clinical objectives while balancing: cost, time, bioavailability, ease of manufacture, stability, and scalability |
| Quality of CMC Leadership |
Improve strategic direction of development program and provide perspective and guidance on each Risk Category described in this Scorecard |
| Timing |
Prioritize CMC activities in a phase appropriate manner, reducing time, cost, and risk associated with the drug development program |
For further information on Pharmatek’s Drug Development Risk Assessment Scorecard, or for help scoring your own compounds in development, please contact Pharmatek at scorecard@pharmatek.com .