Table 2.
Risk classification template: The designed risk classification template used to determine the overall risk class of a generic medicinal product
| Item no. | Aspects to consider | Dosage form affected | Risk assessment guide | Comments |
|---|---|---|---|---|
| RELIANCE | ||||
| API | ||||
| RA1. | CEP/CPQ submission, internal and external reports | All |
CEP/CPQ submitted = 1 if not, are reports from the Authority’s database available = 1 if not, is external reliance claimed = 1 if not, go to RA2 |
|
| RA2. | Specifications | All |
CEP/CPQ submitted = 1 if not, are reports from the Authority’s database available = 1 if not, is external reliance claimed = 1 if not, is pharmacopoeial monograph claimed = 1 if not, is pharmacopoeial monograph available and not claimed = 2 if not, is pharmacopoeial monograph not available = 3 |
If a monograph is available and not claimed, limits for degradants should be pharmacopoeial and process-related impurities should be according to ICH Q3A (R2) guideline. Applicant to provide cross-validation data to demonstrate equivalence |
| FPP | ||||
| RF1. | Internal and external reports | All |
Are reports from the Authority’s database available = 1 if not, is external reliance claimed = 1 if not, go to RF2 |
|
| RF2. | Specifications | All |
If the above is not applicable, are reports from the Authority’s database available = 1 if not, is external reliance claimed = 1 if not, is pharmacopoeial monograph claimed = 1 if not, is pharmacopoeial monograph available and not claimed = 2 if not, is pharmacopoeial monograph not available = 3 |
If a monograph is available and not claimed, limits for degradants should be pharmacopoeial and process-related impurities should be according to ICH Q3B (R2) guideline. Applicant to provide cross-validation data to demonstrate equivalence |
| BE | ||||
| RB1. | Internal and external reports | All |
Are reports from the Authority’s database available = 1 if not, is external reliance claimed = 1 if reports not available = 2 |
|
| Decision point |
If full internal or external reliance is identified, the risk assessment is herewith concluded If partial reliance, such as in RA1, RA2, RF1 and RF2, is identified and reliance pathways are not identified, then move to non-reliance mechanisms below |
|||
| NON-RELIANCE | ||||
| API | ||||
| A1. |
Solubility BCS class |
Solid oral dosage forms |
BCS Class 1/3 = 1 BCS Class 2/4 = 4 |
If bioequivalence is submitted for BCS class 2/4 and equivalence is proven, then score = 2 |
| A2. | Hygroscopicity | Solid oral dosage forms |
Slightly to not hygroscopic = 1 Highly hygroscopic = 2 |
CCS is critical. If Alu-Alu or any blisters are used = 1 When bottles (e.g. HDPE) are used as CCS = 2 |
| A3. | Particle size | Solid oral dosage forms |
No micronisation necessary = 1 If micronisation is conducted and specifications included = 1 If micronisation is required but not controlled (this will be requested) = 2 |
To check if micronisation is required, refer to ICH 3QA decision tree #3 (Only if API is BCS class 2/4); Not applicable if API is fully dissolved during FPP manufacture |
| A4. | Polymorphism | Solid oral dosage forms |
Amorphous form = 1 Consistent polymorphic form manufactured and controlled = 1 Different polymorphic forms produced as a ratio = 2 |
Only if API is BCS class 2/4, Not applicable if API is fully dissolved during FPP manufacture |
| A5. | API load (concentration) | Solid oral dosage forms and semisolids |
High API load (more than 5% of the total mass) = 1 Low API load (less than 5 % of the total mass) = 2 |
For low API load, if the manufacturing process involves wet granulation, uniformity is assured = 1 If manufacturing process involves direct compression, in-process controls should be checked for content uniformity = 1 If content uniformity is not conducted, it should be requested and proven = 2 |
| A6. | Therapeutic index | All |
Wide therapeutic index = 1 Narrow therapeutic index, high load = 4 Narrow therapeutic index, low load = 5 |
Examples of narrow therapeutic index APIs = chloramphenicol, lithium, carbamazepine, phenytoin, digoxin, warfarin, rifampicin, phenobarbital, theophylline.b |
| Repeat for different APIs, if present | ||||
| FPP | ||||
| F1a | Type of dosage form as per dosage form classification (Tran et al. [32]) | All |
Non-sterile solutions = 1 Immediate release solid oral dosage forms = 1 Powders for suspension, not sterile = 1 Semi-solids (ointments and creams) = 1 Sublingual = 2 Buccal = 2 Modified release solid oral dosage forms = 4 Solid oral, immediate release dosage forms for treatment of chronic illnesses = 3 Transdermal = 4 Sterile products = 4 Injectables (products injected directly into the systemic circulation) = 4 Metered-dose inhalation (applied directly to the site of action) = 5 |
|
| F2a | Complexity of the manufacturing process | All |
Non-sterile solutions Measuring; mixing blending = 1 Immediate release solid oral dosage forms, Compression (tablet); granulation (dry and wet); milling; measuring; mixing blending; coating; drying; encapsulation (hard gel) = 1 Powders for suspension, not sterile Milling; mixing blending; measuring = 1 Semi-solids (ointments and creams) Emulsification; mixing blending, Deaeration; heating, cooling; measuring = 1 Sterile products, injectables Aseptic filling-traditional method; form-fill seal, isolation, filtration; lyophilisation, mixing blending, terminal sterilisation, validation, in-process and testing conditions = 4 Modified release solid oral dosage forms Compression (tablet); granulation (dry and wet); milling; measuring; mixing blending, rate-controlling materials, release system; coating; drying; encapsulation (hard gel) = 4 Transdermal Active deposition; coating; extrusion, mixing blending, drying; measuring, primary packaging is critical to dose delivery = 4 Metered-dose inhalations Assembly; filling, Micronisation = 5 |
|
| F3. | Composition in relation to the reference product | All |
If qualitative composition of the reference product is the same = 1 If qualitative composition differs from reference product = 2 |
For qualitative composition that differs from the reference product, assess API-excipient compatibility studies for excipients not in the reference product |
| F4. | Excipients | All |
Well-known and pharmacopoeial = 1 Novel = 5 |
A DMF is required for a novel (non-pharmacopoeial) excipient |
| F5. | Container closure system (CCS) | All |
If CCS is the same as the reference product = 1 If the CCS is critical to accurate dosing = 5 (e.g. metered-dose inhalers) If the manufacturer cannot use the CCS as required by reference or other generic products = 2 |
For CCS that is not identical to the reference or other generic products, assessment of the stability data will prove suitability of container = 1 |
| Repeat for other FPP manufacturers, if present and different | ||||
| BE | ||||
| B1. | Bioequivalence and comparative dissolution with the reference products | Solid oral dosage forms |
Biowaiver submitted = 1 BE and dissolution submitted and bioequivalence proven = 2 If the API(s) is known for bio-inequivalence problems = 4 |
To confirm equivalence check section under results on the BE template to confirm a confidence interval of 80 – 125 % |
Five-point risk scoring scale: 1–very low, 2–low, 3–medium, 4–high, 5–very high
API Active Pharmaceutical Ingredient, BCS Biopharmaceutics Classification System, CEP Certificate of Suitability, CPQ Certificate of prequalification, DMF Drug master file, ICH Q3A International Conference for Harmonisation Q3A, ICH Q3B International Conference for Harmonisation Q3B, HDPE high-density polyethylene.
aIf F1 and F2 are scored as 4, then application is high risk as these aspects carry more weight
bFor the comprehensive list see reference[47]
cThe scores for all rows are assessed once template is completed and Table 3 used to obtain overall classification
RA# reliance for API section, RF# reliance for FPP section, RB# reliance for BE section, A# aspect to consider under API section, F# aspect to consider under FPP section, B# aspect to consider under BE section