This document discusses a technical analysis of discrepancies found in a recent 483 observation, including issues with aseptic practices, visual inspection programs, and media fill programs. It provides background on the author, Palash Chandra Das, who has expertise in qualification and validation, sterility assurance, quality management systems, investigations, and risk management. The bulk of the document then analyzes and provides recommendations regarding the discrepancies observed in the 483 related to particle investigation, manual inspection processes, environmental monitoring, smoke studies, intervention categorization and risk assessment.

1. 483 CASE STUDY
Technical analysis
Chandra Das Palash
Palash.ds@gmail.com
Abstract
Case study consider from a recent 483, mostly we have discussed here the discrepancy
observed in Aseptic practices, Visual inspection program and Media fill program

2. ABOUT AUTHOR
Palash Chandra Das
M. Pharma
LinkedIn Link
Pharmaceutical Chemistry
Core Technical Area: Qualification & Validation , Sterility
Assurance, QMS, Investigation, Risk Management
Palash Chandra Das is the Technical Writer focuses on technical writing including
investigative reports and operating procedures. His passion for writing is displayed in the
many writing sessions he hosts via his Blogs at https://pres.net.in.
Mr. Palash Chandra Das is recognized as an expert in the field of aseptic manufacturing of
parenteral products, and is a frequent presenter at several web conferences and technical
training for Sterile Drug Manufacturing.
He earned his Master’s for Pharmaceutical chemistry from the University of West Bengal
University of technology in India.
Since 2011 Palash has associated with installation, qualification and operation of several
production-lines in standard Clean room Technology as well as in Isolator Technology at
major regulatory facility across India.

3. 483 Analysis
Investigator
Source of particle can be extrinsic, intrinsic or inherent. Based on the nature of particle investigation
to be initiate to identify the root cause. Exact root cause may not be identifiable but probable source
of generation to be identified. Routine trend and defect library some time use as very helpful tool
for investigation.
Inherent: intact therapeutic protein, denatured therapeutic protein, degree of degradation, other
protein component(s)
Intrinsic: silicone, glass, rubber, stainless steel, fibres (cellulose, polyester), etc.
Extrinsic/process related: autoclave tape, gowning materials, Tyvek wrap, etc.
Extrinsic/foreign: hair, insect parts, clothing fragments, metal, paint, etc.
Get article link >>
Unidentifiable material is always add risk to your process. If it is unidentifiable also we should find
the similarity in terms of Symmetrical, asymmetrical/irregular, rigid, thick, thin, fragile, flexible,
malleable, charged, chemical composition, metallic components, surface characteristics, bio
reactivity, leachability, infectivity, sterility, infection risk.
Get article link >>
Sometimes, a small piece of the stopper can be sheared off following needle insertion. This piece of
rubber can be pushed through to the liquid medication and subsequently can be injected into the
patient. This problem is called as “Coring”.
Coring is still an issue in markets globally. Fragmentation tests are carried out to measure the
number of fragments (or “coring”) generated by needles following the insertion to a rubber stopper.
Although coring most likely occurs infrequently, studies have recognised it to be a potential health
hazard with serious implications for the patient. Get article link >>

4. 483 Analysis
Investigator
Gasket replacement frequency is maintaining by number of organization. Although if the particle is
not exactly black then probable source may be filling line , filter medium or product nature. Because
if any particle travel through tunnel it will be charred and become black.
As part of investigation firm verified vial sealing machine and found height did not include during
validation. Same day inspection machine malfunctioning identified and probability of mixed up
during initial set up vials is interpreted.
Vials capped at an insufficient force may leak from the sealing surface. On the other hand, vials
capped at an excessive force may experience cracking and bulging, also risking the integrity of the
closure system.
Get article link >>
RSF tester can be beneficial to establish the sealing force. The function of the Residual Seal Force
Tester is to evaluate seal tightness by measuring the Residual Seal Force in the stopper/seal
combination created as a result of the sealing process.
Get article link >>
Manual inspection process is always a difficult task. Procedure should to be elaborate all the aspect
and proper training need to be ensured. Otherwise it will result number market complaint as well as
increase the patient risk.
Get article link >>

5. 483 Analysis
Investigator
Any new identified defect during process or market complaint should to be part of your defect
library. And should to be incorporate to your inspection training program.
Get article link >>
Rationalization is very important during finalization of any test in qualification protocol. Selection of
NVPC counting should to be based on the criticality. If number of HEPA unit representing an area
then risk based approach to be followed to identify the location for NVPC.
Get article link >>
In case selection of fixed particle counter probe in Grade A area , locations normally not more than 1
foot away from the work site, within the airflow, and during filling/closing operations. Some
operations can generate high levels of product (e.g., powder) particles that, by their nature, do not
pose a risk of product contamination. It may not, in these cases, be feasible to measure air quality
within the one-foot distance and still differentiate background levels of particles from air
contaminants. In these instances, air can be sampled in a manner that, to the extent possible,
characterizes the true level of extrinsic particle contamination to which the product is exposed.
Initial qualification of the area under dynamic conditions without the actual filling function provides
some baseline information on the non-product particle generation of the operation.
Get article link >>

6. 483 Analysis
Investigator
It is important for area qualification and classification to place most emphasis on data generated
under dynamic conditions (i.e., with personnel present, equipment in place, and operations
ongoing). An adequate aseptic processing facility monitoring program also will assess conformance
with specified clean area classifications under dynamic conditions on a routine basis.
Evaluation of smoke study is equally important. Your study should review the study CD/DVD for
follow criteria,
 Studies should demonstrating Laminarity over the product path
 Sweeping action should to be away from the product path
 Activity/intervention should to be performed as per procedure
 Any Turbulence observed in smoke flow shall be relook
 Airflow should demonstrate unidirectional path
 Airflow should to be from supply and evacuate through return
 Clip should to demonstrate the complete interventions
 Adequate density of Smoke is preferred
 Continues smoke flow during intervention is preferred
 Visibility of intervention should to be part of evaluation
If in case poor visibility mentioned the reasons e.g. Reflection / less lighting/denser smoke and
repeated the study.
Get article link >>
Sealing station NVPC normally firms are not performing for getting false pick during process. But in
bunging station for liquid or in case of lyophilized unloading station NVP monitoring are considering.
Get article link >>
Intervention are categorized as inherent and corrective, previously it called as routine and non-
routine. Inherent means as a part of process it is mandatory to intervene the within the Grade A
airflow. Corrective means apart from routine intervention if any correction action we are performing
during process. Is may be happened due to machine break down or any other adjustment. Always

7. 483 Analysis
Investigator
there a possibility of new corrective intervention , that new intervention to be capture during air
flow visualization study as part of interim action and finally need to be capture in media fill program.
A latest PDA technical paper discussed about risk assessment of intervention. Assessment should to
be based on the three aspect.
Proximity: How much distance of your intervention from critical process path? E.g. adjustment of
load cell
Durability: How much time takes to perform the intervention? E.g. Fill volume adjustment
Repeatability: How many time we need to perform during batch? E.g. Rubber stopper or seal re-
supply
Number of firms are identified with same problem. Pre-start up activity does not capture in the
equipment log. It is very important machine set up, prestart up checks should to be part of batch
activity. Environmental monitoring of Grade A filling area should to be consider during aseptic
assembling.
All these interventions are highly recommended to demonstrate during airflow visualization and
need to be a part of media fill program.
--X--