Design, Trust & Control of Sterile Manufacturing

Obaid Ali & Roohi B. ObaidCivil Services Officers, Government of Pakistan

12th March 2016, Saturday, Karachi

08th

Technical Meeting / Forum

Sterile Manufacturing

Part II 4

Sensitivity Instability Aseptic processing

But no packaging

component

Terminal Sterilization vs. Aseptic Processing

Terminal Sterilization vs. Aseptic Processing

It is a well accepted principle that sterile drugs should be manufactured by aseptic

processing ONLY when terminal sterilization is NOT feasible

Design, Trust & Control of Sterile Manufacturing

Regulatory Observations and Comments

Case Study (1)

From US-FDA for Sun Pharma Dec 2015

Smoke Studies

Unidirectional Air Flow studies under Dynamic Conditions to determine how MOVEMENT of Personnel & Air pose risk to STERILITY of product

Significant airflow turbulence

Lack of dynamic simulation of

critical intervention

No studies during manual aseptic

transfer

Inadequate evaluation of

pattern in stopper area

Turbulence around stopper

Without smoke studies to demonstrate unidirectional airflow over all aseptic operation & processing steps, one cannot prove that the process is designed to prevent microbiological contamination or provides adequate assurance of product sterility

Take home message

Case Study (2)

From US-FDA for Mylan Labs Aug 2015

Gowning in Aseptic Area

Aseptic garments worn in the filling area were non-integral. The inspector observed 7 of the sterile gowns with tear or holes, and 8 of the gowns with loose threads. 8 Sterile booties were also observed with tear or holes and 11 had loose threads. 2 sterile hoods with tears or holes, and 12 with loose threads were also observed.

Non-integral aseptic garments

Procedure requiring production personnel to examine garments for tears, holes etc. was

available

Inspector found that these checks as per procedure were not

performed

No assurance that gowns are suitable for aseptic

manufacturing

Failure to follow the procedures leads to lack of assurance that manufacturing environment is maintained in a state of control suitable for aseptic processing.

Take home message

Case Study (3)

From US-FDA for Agila Specialities Aug 2015

Inappropriate Sampling Plan for

Environmental Monitoring

A robust sampling plan was not in place as part of environmental monitoring plan. No representative non-viable particle (NVP) monitoring data supports firm’s current (ISO5) classification for the product path from X to Y, which transfers product during aseptic processing.

NVP probes were placed on X surface instead of near the working area

Placing probes away from working area

means inability to detect NVPs where sterile

drugs are exposed during aseptic processing

Furthermore, inspector found that transferring vials from the filling

suite to the X can take up to Y time.

This extended exposure time may increase

contamination hazards

It is essential that the sampling plan include areas where product is exposed to the environment, and is at greater risk of contamination.

Take home message

Case Study (4)

From US-FDA for Agila Specialities Aug 2015

Failure to identify Source of Microbial

Contamination

The source of gram-negative contamination in your ISO 7 area was not identified and appropriate corrective actions and preventive actions were not implemented

In the ISO-7 Suite, Pseudomonas, sp. during passive

air sampling collected from firm’s passage way, in X rooms

Y and Z was identified

The potential routes of contamination were not

evaluated.

The evaluation of environmental microbial data should not be narrowly limited to specific lots or events

Trend analysis, identifying sources of contamination, and risk assessment are essential to maintain adequate microbiological control

Take home message

Case Study (5)

From US-FDA for Promed Exports Aug 2013

Inadequate system for cleaning &

disinfecting aseptic processing areas

A sporicidal disinfectant for cleaning inside of the Class 100 (ISO 5) filling areas is not used.

The inspection documented that the firm uses XXX alone, which

is not effective against spore-forming organisms such

as Bacillus spp.

The September 2011 media fill failure investigation for

the X Line Y identified the contaminating organism

as Bacillus pumilus.

Additionally, the disinfectant X on surfaces inside the Class 100 (ISO 5) area including Y was not sufficiently

evaluate

It is essential that the sporicidal agent be used regularly to ensure a suitable ISO 5 (Class 100) environment

Take home message

Case Study (6)

From US-FDA for Wintac Feb 2012

Poor aseptic practices by

Personnel in aseptic processing areas

Poor aseptic practices during the filling of sterile X products were demonstrated by operators such as

An operator performing critical aseptic operations with exposed skin at the forehead, posing an

unreasonable risk of the product becoming contaminated

Operators moving very quickly in the aseptic area, which may create

unacceptable turbulence in the area, and disrupt the unidirectional airflow

Operators leaning halfway in and out of the class 100 area

while performing interventions over opened

bottles

Operators must be trained for the particular function/operation and the effectiveness of training be monitored at regular intervals

Take home message

Case Study (7)

From US-FDA for Hemofarm Jun 2012

Unreliable Environmental

Monitoring Data

Environmental monitoring (EM) data is not reliable. This is a serious deviation, as the ability to detect microbial contamination in the manufacturing environment during aseptic processing is fundamentally compromised

The firm used dried/desiccated media agar plates for

environmental monitoring testing used to support the release of

batches.

On November 15, 2011, it was documented that 155 of a total of 247 media plates evaluated (more

than 50%) were dried.

The use of dried agar plates, which do not reliably support microbial growth, to recover microbial contamination is

inadequate.

1

On November 14, 2011, the FDA investigator observed desiccated environmental monitoring plates in the

incubators

However, the analysts only recorded the results as dried

media but not the counts from the plates (if any)

On this same day, the FDA investigator observed plate “X” sampled on November 9, 2011, to have growth of 1 Colony Forming Unit (CFU)

However, the firm documented the result of this plate’s reading as

"SAUSEN MEDIUM", dry medium, and failed to report the

microbial growth.

2

Environmental monitoring data for January 2009 through October 2011 contains documentation of only two action limit excursions in the Grade A

manufacturing areas.

In apparent contradiction, during an FDA visit to the microbiology laboratory on November 14, 2011, nine plates, collected as part of the

environmental monitoring program from the Grade A manufacturing area were found inside an incubator in the microbiology laboratory with

visible growth of microorganisms.

3

The environmental sampling and testing program procedure is inadequate because it fails to adequately identify (e.g., with diagrams) the locations from which the surface samples are

collected

In addition, the firm do not collect sufficient active viable air samples and dynamic non-viable particulate air samples

from the critical area during manufacturing

4

The agar level on surface contact plates (used for surface environmental and personnel monitoring sample testing) was below the rim of the plates creating the

possibility that the agar would not have contact with the surface intended to be sampled

5

The bioburden testing of the X components is inadequate. It lacks adequate controls to assure

that the melted agar is sufficiently cool to prevent cell death of viable

microorganisms

Specifically, the analyst determines by hand touch, without any instruments, the

adequacy of the temperature of the melted agar medium used for the bioburden testing of the API, X and Y before pouring the agar

into the plates and mixing it with the samples

The firm’s response indicated that a study was completed to determine the time required for

the agar media to cool to the temperature of the water bath (X°C) prior to use of that media in

pouring microbiological plates

The response is inadequate because it did not describe the

study method, laboratory controls used for temperature monitoring, and time controls

during the study

6

EM data is critical to monitor the acceptability of the environment that the sterile drug and its container-closure components are exposed to during processing, and assure that these conditions consistently safeguard product sterility

Take home message

Case Study (8)

From US-FDA for Mc Guff Pharmaceuticals, Dec 2010

Inappropriate Autoclave

Qualification

Qualifications of the AA autoclave and the BB oven are inadequate in that the equipment have not qualified with representative loads

The firm’s practice is to qualify the equipment using minimum loads as opposed to actual loads during routine operation (e.g., BB oven was qualified to depyrogenate glass vials using X tray when the actual load is a

maximum of Z trays)

In addition, the use of biological indicators and penetration

thermocouples in the qualification studies are inadequate

Any penetration thermocouples were not used during the qualification of GetingeAA autoclave since February X, nor the

use of biological indicators was incorporated

During the maximum load configuration study, only a X penetration thermocouple were used and the firm failed to use any

biological indicators

Without appropriate qualification of the equipment, there is no assurance of the consistent quality of product being manufactured

Take home message

Case Study (9)

From US-FDA for Genzyme, Feb 2009

Inappropriate HVAC Qualification

Air flow pattern testing studies, executed in August of 2007 during the operational qualification of the HVAC system for fill suite XXX, do not fully demonstrate air flow movement away from work surfaces during representative personnel activities and manual simulations of the aseptic filling processes

Operations & practices not preformed during air flow pattern testing studies

include: Critical aseptic connections

Routine functions of aseptic core operators, for example: Manually placing stoppers or

reorienting stoppers using forceps for filled vials

Withdrawing unfilled vials from the filling line for weight checks

Redirecting filled vials typically with stoppers on the exit feed

wheel

Cont’d

Unidirectional air flow over the rotary in-feed table

Opening the lyophilizer door or the automated double doors

into the aseptic preparation area

Active viable air sampling

Without appropriate qualification of the HVAC, prevention of microbiological contamination of the product cannot be assured

Take home message

Case Study (10)

From US-FDA for Sanofi, Germany Feb 2011

Inappropriate HVAC Qualification

Separate or defined areas or such other control systems as necessary to prevent contamination or mix-ups during aseptic processing have not been established

e.g. the airflow velocity inside critical areas of the aseptic processing operations

of Line X was found unacceptable

The documentary evidence of in-situ air pattern analysis (e.g.,

smoke studies) reviewed during the inspection

confirmed this condition.

The firm should be able to demonstrate unidirectional airflow and sweeping action

over and away from the product under dynamic conditions

Proper design and control prevents turbulence and stagnant air in the critical areas. It is crucial that airflow patterns are evaluated for turbulence that can act as a channel for contamination, and that any deficient conditions are addressed.

Take home message

Design, Trust & Control of Sterile Manufacturing

Questions and Answers