Module 1 cGMP- Sample Case Studies

Small Volume Parenteral (SVP) Poor sealing of flip off seal

Dosage form: Small volume parenteral (SVP)

Therapeutic category: Analgesic (To treat moderate pain after surgery)

Defects:

• Poor sealing of infusion bottle affecting sterility of the product.
• The rubber bung comes out while trying to break open flip off seal (as reported by ward nurse).

Category of complaint: Critical

Probable root causes:

• Tilt/loose cap and flip off seal because of improper crimping.
• Size mismatch (possibility may be a short body of seal due to which the crimping is improper).
• Hardening of rubber bung due to storage.
• Improper sealing of bottle probably due to lack of crimping/sealing force.
• Inadequate visual inspection by operators or by untrained operators.

Clinical significance: Sterility of the product compromised and is a risk to patient’s health. It may also lead to product deterioration and unwanted adverse effects.

Tablets Melted/softened enteric coated tablets

Dosage form: Enteric coated tablets

Therapeutic category: Antiulcer and antiemetic

Defects: Two enteric coated tablets found to be melted/softened within intact blister pocket.

Category of complaint: Critical

Probable root causes:

• Sealing temperature set during lidding process may be high.
• Tablets were exposed to excess heat because of higher dwell time.
• In-process Quality check was not done adequately.
• Space between the product-containing cavities, as well as to the outer edge of the blister may be less during the sealing.

Clinical significance: Active Pharmaceutical Ingredients (APIs) of the product might undergo deterioration because of high sealing temperature. As a result, adverse events may increase. The release profile may be altered, and the patient may not get desired pharmacological actions for their intended purpose.

Tablets Batch to batch color variation of film coated tablets

Dosage form: Film coated tablets

Therapeutic category: To treat schizophrenia and acute manic episodes

Defects:

• Color variation observed from batch to batch.
• A classic example for dark, medium and light shades.

Category of complaint: Major

Probable root causes:

• Color variation can be due to an error in weighing coloring agents or concentration of the coloring dye used and error during processing.
• It can be due to improper spraying process, which may differ in the spray time or spray quantity.
• Improper mixing of colored dye solution.
• Variation of the frequency or duration of appearance of tablets in the spray zone or the size/shape of the spray zone.
• Insufficient coating.
• Migration of the soluble dye’s plasticizers during the process of drying,
• Inadequate monitoring of critical coating parameters.

Clinical significance: This type of defect can create a dilemma in patients due to changes in color of dosage form and may intervene with patient adherence to drug treatment regimens.

Capsules Two empty blister pockets in 4s pack

Dosage form: HPMC Hard gelatin capsules

Therapeutic category: Source of Vitamin D3

Defects: Two empty pockets found within an intact blister pocket of 4s pack

Category of complaint: Major

Probable root causes:

• IPQC checks were not done adequately.
• Intermediate product line clearance was not properly performed.
• Final QA approval was given without a proper inspection.

Clinical significance: Patient acceptance will decrease, and this will directly affect the therapeutic outcome due to psychological effects. The number of doses may get reduced due to the empty pockets and the patient may not refill the reduced doses, which will affect its therapeutic outcome.

Capsules Sandwiched capsule between foil and PVC film

Dosage form: Capsules

Therapeutic category: Anti-cancer

Defects: One capsule sandwiched between the printed foil and PVC film.

Category of complaint: Critical

Probable root causes:

• Packaging machine settings were not set appropriately.
• Failure during in-process QC checks.
• Poor inspection process.
• Poor training and development of personnel.

Clinical significance: Actual ingredients may not be available in the sandwiched capsule and the required quantity of the drug may not be available for the therapeutic activity. It may also lead to a decrease in its clinical effectiveness. This defect may also lead to the missing of dose and deterioration of API.