Table 1.
Distribution of main reasons for refusal to approve generic and similar pharmaceutical drug products.
| Classification (general area and specific categories) | Quantity (n) | % |
|---|---|---|
| Drug product quality control | 67 | 13.3% |
| Analytical method validation | 26 | 5.2% |
| Absence of impurity control | 7 | 1.4% |
| Absence of obligatory tests | 6 | 1.2% |
| Absence of adequate justification for proposed limits for impurities | 5 | 1.0% |
| Partial analytical method validation | 5 | 1.0% |
| Reproved method or specification | 4 | 0.8% |
| Wrong calculation | 3 | 0.6% |
| Others | 11 | 2.2% |
|
| ||
| Drug product stability study | 62 | 12.4% |
| Absence of impurity control | 17 | 3.4% |
| Refusal due to reproved quality control | 8 | 1.6% |
| Nonstability indicating assay method | 7 | 1.4% |
| Incomplete study | 5 | 1.0% |
| Absence of obligatory quality control tests | 4 | 0.8% |
| Disagreement between dissolution specification and results | 4 | 0.8% |
| Absence of reconstitution stability study | 3 | 0.6% |
| Nonspecific method for degradation products | 2 | 0.4% |
| Others | 12 | 2.4% |
|
| ||
| Deadline accomplishment | 50 | 9.9% |
| Absence of clone drug product petition | 33 | 6.6% |
| Nonaccomplishment of objections answer deadline | 13 | 2.6% |
| Others | 4 | 0.8% |
|
| ||
| API quality control, by drug product manufacturer | 41 | 8.2% |
| Analytical validation problems | 13 | 2.6% |
| Absence of method or analysis of residual solvents | 7 | 1.4% |
| Absence of method or analysis of impurities | 6 | 1.2% |
| Absence of obligatory tests | 4 | 0.8% |
| In disagreement with compendial standard | 3 | 0.6% |
| Absence of certificate of analysis | 2 | 0.4% |
| Others | 6 | 1.2% |
|
| ||
| Active pharmaceutical ingredient (API) | 41 | 8.2% |
| API quality control faults | 25 | 5.0% |
| Lack of API polymorphic form proof | 5 | 1.0% |
| Lack of synthesis route | 3 | 0.6% |
| Nonaccomplishment of objections answer deadline | 2 | 0.4% |
| Absence of documents | 2 | 0.4% |
| Others | 4 | 0.8% |
|
| ||
| Production report | 29 | 5.8% |
| Production report did not include all stages of production process | 8 | 1.6% |
| Production process was nonreproducible | 6 | 1.2% |
| GMP noncompliance | 5 | 1.0% |
| Different batch sizes | 3 | 0.6% |
| Generic formulation with different API from the reference drug | 2 | 0.4% |
| Others | 5 | 1.0% |
|
| ||
| Pharmaceutical equivalence | 27 | 5.4% |
| Analytical method validation | 10 | 2.0% |
| Reference drug product with unapproved efficacy and safety | 4 | 0.8% |
| Reproved quality control method | 3 | 0.6% |
| Reproved | 4 | 0.8% |
| Others | 6 | 1.2% |
|
| ||
| API stability studies | 23 | 4.6% |
| Lack of stability studies on Brazilian climatic zone | 16 | 3.2% |
| Nonstability indicating methods | 4 | 0.8% |
| Absence of accelerated stability study | 2 | 0.4% |
| Others | 1 | 0.2% |
|
| ||
| Dissolution | 23 | 4.6% |
| Nondiscriminative methods | 10 | 2.0% |
| Inadequate dissolution quality control specification | 4 | 0.8% |
| Others | 9 | 1.8% |
|
| ||
| Bioequivalence studies | 17 | 3.4% |
| Reproved | 10 | 2.0% |
| Absent | 5 | 1.0% |
| Studies done with drug products that are no longer considered reference | 2 | 0.4% |
|
| ||
| Excipients quality control | 16 | 3.2% |
|
| ||
| Preliminary analysis | 16 | 3.2% |
|
| ||
| Documentation | 15 | 3.0% |
| Absence of current GMP certificate | 11 | 2.2% |
| Others | 4 | 0.8% |
|
| ||
| Drug product photostability | 13 | 2.6% |
| Absent | 7 | 1.4% |
| Absence of degradation products control | 5 | 1.0% |
| Others | 1 | 0.2% |
|
| ||
| Minor reasons | 61 | 12.7% |
|
| ||
| Total | 501 | 100.0% |