Pharmaceutical MicrobiologyMultidisciplinary Integrated Approach in Drug Manufacturing

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

(4/5) Case Studies

Personnel Practice

Environmental Control

Operational Design

Reference: Richard L. Friedman, FDA, CDER, DMPQ

Aseptic Processing of a Sterile Active Pharmaceutical Ingredient (API)

Case Study

1

50 Finished product lots recalled

Background

API shipped Received Assurance of sterility

Sterility failures trend

API lab & Finished good lab

API mfg relied heavily on manual

manipulation

cGMP Issue

Finished dosage form site compliant for cGMP

Design of process … adequate protection from microbial contamination

Major GMP issue at API site

Manual Opera

Media Fill: Used very high pH medium Growth Promotion Capability not evaluated

Media dried at 85 to 95℃ Representative temp was 20 to 25 ℃ ?

Quality System

Production system most deficient

Process simulation inadequate

Process simulation insensitive

Loss of media fill basic benefit of

prompt detection

Sound scientific foundation support

was absent

Reliability of daily decisions under

question

Quality System

Product development & process validation

intended to yield

Important information about product & process

Poorly conceived study and conclusion based on assumption

may lead to

Erroneous process design decision & consequent risk to

product quality

Rational experiment design is required

Continuous learning throughout the life

cycle

Intensive aseptic activity by personnel considered to be the root of contamination

Ultimately ended up with modification in process to include semi-closed process concept as well as automation

Case Study

1Outcome

Assuring Container Closure Integrity throughout Manufacturing

Case Study

2

Recall of multiple lots under Class I

Background

Contamination found

Enterobactercolacae

Other micro-organisms also

found

Xanthomonasmaltophilia

Adverse drug eventsSepticemia

cGMP Issue

Container closure integrity problem identified

Cleaning of floor with uncontrolled shower of tap water done

Finished product dropped

Sealed vials exposed to tap water ? ? ?

Quality System

Packaging & labeling system

deficientPoor handling sealed glass

Rough handling

Sub-visible hairline cracks

Contamination confirmed

Same organism found in water

tank

Quality System

Critical GMP concept required to be reinforced

Every production phase through

packaging must be robust

Assure proper design of

manufacturing operations

Assure proper control of

manufacturing operations

Assure proper maintenance of manufacturing

operations

Continuous learning

throughout the life cycle

Poor & rough handling

Caused septicemia to several patients

Case Study

2Outcome

Extensive Aseptic Interventions by Personnel

Case Study

3

Shut down of Manufacturing Facility

Background

Meda fill-60% units found contaminated

Minor correction to satisfaction 3 media fill runs

2nd media fill with high level of

contamination

Isolate of both failures was common skin borne microbes

(Staph. Cocco)

Sterility failure also occurred in last 6

months

cGMP Issue

Multiple skilled manual interventions in process

These steps posed significant risk to the product

Significant manual interventions

Inadequate aseptic gowning by personnel ? ? ?

Quality System

Initial minor corrections

3 consecutive media fill

Personnel performance of

aseptic connections

Personnel performance of

aseptic manipulations

Personnel performance at bulk stage …..

Design flaw in gowning

Knowledge, Ability & Skills

……equipment connection changed to Sterilized in Place (SIP)

Case Study

3Outcome

Migration of contamination liberated during Facility Construction

Case Study

4

Manufacturing Operation Suspension

Background

Major construction in a clean room for

1 month

Next to personnel entry airlock

(gowning area)Media fill failure

Initial investigation concluded source from non-sterile

unit

Corrected the apparent root cause

Again failure of media fill

cGMP Issue

Did not assess the risk posed by construction activities

Bacillus species

Spore forming bacteria found

Same in both media fills ? ? ?

Quality System

Production & Quality system was deficient

Change was not carefully evaluated

Migration of contamination is not uncommon

Moving of walls is a common

culprit

Spore formers liberated into

the clean roomPotential impact

not evaluated

Deviation & Change Control

Implement special precautions and increase monitoring to detect any drift in environmental control

Case Study

4Outcome

Inadequate System of Environmental Monitoring

Inadequate aseptic processing environment, e.g. No viable air monitoring inside of the Class 100 (ISO 5) filling barrier on the xxx Line (A critical area where drug product and

pre-sterilized components are exposed)

Promed Exports, Aug 2013

Inadequate System of Environmental Monitoring

Outside of the line xxx filling area, the three air samples taken in the Class 100 (ISO 5) area were not taken under dynamic

conditions. These active samples were instead taken after line set-up and before any filling

Promed Exports, Aug 2013

Lesson Learned

It is important to collect air samples that adequately

represent filling conditions

Inappropriate choice of Disinfectant

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

not effective against spore-forming organisms such as Bacillus spp.

The September 2011 media fill failure investigation for the YYY Line identified the contaminating organism as Bacillus

pumilus.

Promed Exports, Aug 2013

Inappropriate choice of Disinfectant

Moreover, the XXX disinfectant was not sufficiently evaluated on surfaces inside the Class 100 (ISO 5) area

Promed Exports, Aug 2013

Lesson Learned

The use of sporicidal disinfectant is essential for cleaning in the

critical areas where drug product & pre-sterilized components are

exposed

Unreliable Environmental Monitoring Data

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.

Hemofarm, Jun 2012

Unreliable Environmental Monitoring Data

Sufficient active viable air samples and dynamic non-viable particulate air samples from the critical area during

manufacturing are not collected

Hemofarm, Jun 2012

Lesson Learned

The EM sampling & testing procedure should identify & sufficiently cover the sample

locations for viable & non-viable particles

Unreliable Environmental Monitoring Data

There is lack of adequate control 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 bio-burden testing of the API, XXX and

YYY, before pouring the agar into the plates and mixing it with the samples

Hemofarm, Jun 2012

Lesson Learned

Inadequate Procedure for Plate Preparation

sterile preservative-free ibuprofin L-lysine at

17 mg/mL in a single-use glass vial

in premature infants no more than 32 weeks

gestational age

Two batches of this product were

voluntarily recalled by the manufacturer,

Lundbeck

interaction between the product and the Type I borosilicate glass vial

It substitutes for the aluminum oxide

forming an ibuprofen aluminum hydroxide

salt as particulate

Be Alert

Thanksoarohama@gmail.com