Visual Inspection of Parenteral Products

Prepared by: Sambhujyoti Das

General Process Flow

DISPENSING RMs MANUFACTURING FILTRATION (STERILIZATION)

FILLING & SEALING

VISUAL INSPECTION

DISPENSING OF CONTAINERs /

CLOSUREsWASHING STERILIZATION /

DEPYROGENATION

100% filled containers are

inspected.

Slide No. 2

Why to inspect?

To detect and eliminate defective units from the lot.

Extraneous Particulate matter in solution.

Product precipitates.

Sealing / crimping defects.

Cracks / non-integral container-closure.

Volume variations.

Regulatory requirement – “Injectable products should be essentially free from any visible particles” USP <1>, <790> & <1790> , EP, JP.

Slide No. 3

The Particle Family

VISIBLE PARTICLES

EXTRINSIC INTRINSIC INHERENT

o Not part of product (or non product contact).

o From foreign and unexpected sources.

o Fibers (e.g., cellulous), clothing fragments, hair, rubber, metal, plastic, and paint.

o Bioburden is unknown and uncontrolled.

o Greater risk.

o Part of product / package (product contact surfaces).

o Known sources.o Glass, stainless steel, rubber

from stoppers, and gasket material.

o Can change in the product over time.

o Intrinsic to extrinsic.

o Expected from the drug formulation.

o Adjuvant material in suspension products, certain excipients in serum albumin, proteinaceous aggregates.

o Patient safety impacts should be analysed.

o Should be in specification.

Slide No. 4

Guess the particle type

Polyester fibre Elastomer particle(From aseptic gown) (From Rubber Stopper)

Slide No. 5

The Irony

REGULATION PRACTICAL SITUATION

Probabilistic inspection process

Unrealistic Particle free

process

100% Elimination of

Particle

100% Particle free

Confused?

Slide No. 6

Visual Inspection System

Slide No. 7

Manual Inspection Visual inspection against black & white

background.

Illumination at the inspection point by two 13-W / 15-W fluorescent lamps.

Intensity between 2000 and 3750 lux.

Gently swirl and/or invert each unit.

Ensure that no air bubbles.

5 s against each of the backgrounds.

Presence of any particles should be recorded. Slide No. 8

Automated Inspection Similar optical inspection like manual.

Same or greater sensitivity (not all).

Better consistency.

Better efficiency with higher output.

Often higher false rejection rate.

High cost, limited adaptability.

Standardization / validation intensive.

Slide No. 9

Particle Catalogue

Inspector’s ViewMagnified View

Slide No. 10

Particle Size vs Detectability

Particle Size % POD

>200 µm 100%

<100 µm 25% - 70%

<50 µm <5%

Detection Variables: Illumination (intensity, glare), contrast, duration (inspection time, rate), agitation, number of particle, product type, container type. Slide No. 11

Post Inspection Sampling Mandatory sampling and inspection after

100% visual inspection.

Sampling plan as per ANSI/ASQ Z1.4 – 2008 (or ISO 2859-1): General Inspection Level – II, Single sampling plans for Normal inspection with an AQL of 0.65%.

Batch releasing criteria: NMT the specified number of units contains visible particulates.

Special level sampling (reduced sample quantity) for destructive inspections (for powder filled, lyophilized products, coloured containers, etc.).

AQL Failure

Is the test Destructive

?

Investigation

Re-inspection of 100% units

Batch Rejectio

n

Yes

No

Perf

orm

AQ

L in

spec

tion

Slide No. 12

Particle Separation, Identification and Characterization

Manufacturers should have knowledge on their particulate matter rejections.

Type of particles.

Source of each particle type.

Routine trend / capability of particulate rejections.

Morphology of each type of particle.

Chemistry of each particle type.

Manufacturers should have comprehensive particle control and monitoring strategies in place.

Slide No. 13

Particle Separation, Identification and Characterization

Detection by Inspection

(Optical visual inspection)

Verify & Isolate(Capillary

withdrawal / Filtration)

Characterization

(Size, shape, morphology, colour, etc.)

Identification(FTIR, Raman,

EDS, etc.)

Remediation / Control

(Investigation, CAPA)

Slide No. 14

Particle Isolation

Capillary withdrawal method Filtration method

Slide No. 15

Characterization (Microscopic study)

Cardboard Tyvek Rayon

Human Hair Polyester

Slide No. 16

Identification (FTIR Spectra)

Cardboard

Tyvek

Rayon

Human Hair

PolyesterSlide No. 17

Product Recalls

Lack of Sterility Assurance

22%

Visible Par-ticles22%

Impurities / Degradation9%

Other47%

USFDA Sterile Injectable drug recalls (2008 – 2012)

Slide No. 18

• Sagent Pharmaceuticals, Inc. has initiated the voluntary recall of one lot of Oxacillin for Injection, USP, 10 g to the user level due to the receipt of a product complaint for a single vial containing small, dark particulate matter found within the solution after reconstitution. (Date: 18 Aug. 2016).

• Hospira issues a voluntary nationwide recall for one lot of 0.25% Bupivacaine Hydrochloride Injection, USP due to the presence of particulate matter within a single vial. (Date: 8 Aug. 2016).

• Teva Pharmaceuticals initiates voluntary nationwide recall of 7 lots of Amikacin Sulfate Injection USP 500 mg/2 mL and 1 Gram/4 mL vials due to potential of glass particulate matter. (Date: 2 Aug. 2016).

• PharMEDium issues voluntary nationwide recall sterile preparations (Bupivacaine HCl) due to the presence of glass particulate matter. (Date: 5 May 2016).

Product Recalls

Slide No. 19

• Must establish a maximum allowable reject rate.

• Must control re-inspection of product, including when appropriate, inspection conditions and number of re-inspections permitted.

• Inspectors must be trained and training documented.

• Inspectors must be periodically recertified.

• Training and certification conditions must align with routine 100% inspection conditions.

• Address inspection fatigue during qualification.

• Must conduct thorough investigations. Identify particulate matter when performing investigations.

• Must use statistically sound sampling plan(s) for AQL inspection.

•

USFDA 483 Trends

Slide No. 20

Any Questions?

Every closed eye is not sleeping, and every open eye is not seeing.

Slide No. 21

• Particulate Matter in Injections – USP 39, General Chapter <788>.

• Visible Particulates in Injections – USP 39, General Chapter <790>.

• Visual Inspection of Injections – Draft USP Chapter <1790>.

• Recall Data, Steven Lynn, FDA Office of Manufacturing and Product Quality, March,14, 2013.

• Warning Letters 2016 - www.fda.gov.

• PDA Visual Inspection Forum, by John G. Shabushnig, Ph.D. Pfizer Global Quality Operations March 9, 2011.

• A Global Association PDA Update on Technical Reports, recent Projects 2015.

• Manual Visual Inspection Scientific Approach to Determine Particles Probabilistic Detectability – by Luis Aviles at Interphex, Puerto Rico, 2016.

References

Slide No. 22