Microbiology and Auditing

Don Singer

ASQ Northeast Pharmaceutical GMP/Quality Conference 2011

Through the eyes of a Microbiologist

Microbiology Audit = Inspection / Investigation

Systematic Auditing

• Planning

• Right People

• Tools

• Appropriate Objectives

Auditing approach

Corporate design or policy

• Team

• Independent

Purpose

Quality Systems

Build robustness into your quality systems

cGMPs

Types of audits with Evaluation of Microbiological control

• Contract manufacture

• Contract microbiology laboratory

• Excipient manufacturer

• Active ingredient manufacturer

• Combination of any of the above

• Internal manufacture or laboratory

Quality Systems Inspection

Quality system

Production system

Laboratory controls system

Materials system

Packaging and labeling system

Facilities and equipment system

Microbiological Quality Risk Management

• Dosage form

• Laboratory tests

• Materials management

Risk by route of administration

Low

HighParenteral

Tablet, Capsule

Ophthalmic

Liquid-filled capsules

Wound topicals

Topical ointment

Inhaled - MDI

Inhaled - DPI

Intranasal solution

Topical cream

Nebulizer solution

Otic

Oral solutions, suspensions

Lab tests risk from impact of results

High

Low

Sterility Test

Bacterial endotoxin test

Antimicrobial Preservatives Effectiveness Test

Biological assays

Microbial enumeration and Specified microorganisms tests

Microbial identification

Media growth promotion

Materials risk of contamination

High

Low

Animal or plant origin (e.g. lactose)

Synthetic origin (e.g. povidone)

Mineral origin (e.g. Talc)

Mineral origin (e.g. dyes, aromatics)

Semi-synthetic origin (e.g. captisol, HPM)

Unprocessed

Highly processed

Some bioburden reductionprocessing

ClassificationManufacturing process

Audit Expertise

What is a QC Microbiologist?

Knowledge Base :

Science

Origin and Growth

Control

Microbiological Science

Origin and Growth

• Water (H2O)

• Nutrition (CHO, CHON, CHOOH, minerals, etc.)

• Presence or absence of components of air

Other Growth Factors

• pH

• temperature

• osmotic conditions

• light

Microbial Origin and Survival

• moderate to extreme environments

• solid to liquid

• dense to dilute

• atmosphere, humans and other living organisms (animals - vegetation), water, soil

Role of a QC Microbiologist

Design for microbiological control

Monitor to continuously evaluate

ControlHow to manipulate the environment

• Understand microbial growth limitations

• Determine how to reduce or eliminatemicrobial growth

• Understand dynamics of environment and microbiological growth / survival

Understand Thoroughly?

Do you have the appropriate background and experience for microbiological investigation?

If you do not, then partner with a Microbiologist

Tools to Assist

• cGMPs, guidance docs, pharmacopeias

• Quality tools such as

Useful Quality Tools

• Assessment checklist or survey (developed by your Microbiologist colleague)

How does Risk fit Inspection decisions?

• High risk – on-site inspection mandatory

• Moderate risk – questionnaire assessment or on-site inspection

• Low risk – questionnaire

Process flow chart

Release of raw materials

Fermentation

Centrifugation

Chromatography

Bulk substance

Filtration

Final packaged product

Excipients Water

Micronization

Separation

Drying

HydrationWater

Sterile filtration

Filling

and

Process analysis

Details of Process with Controls

• HACCP plan

• Perform a virtual HACCP analysis using tour, procedures and assessment survey

• Amount of detail depends on level of risk

Audit Findings Template

• Same document format as Lead auditor

Or

• Modified document for notes during audit

For efficiency and clarity.

• Agreed on format with Lead auditor

Objectives

I perform an audit with these intended goals:

1. Determine quality systems in place for microbiological control

2. Determine level of knowledge and capabilities of audited site

3. Determine if continuous improvement is part of culture

Objectives (cont.)

4. Determine if culture matches ours

5. Share knowledge and perspective with client where adds value

6. Develop a relationship based on respect, shared learning, communications

Right People Participants

To ensure that adequate and timely information is generated during an audit

Questions should be directed to the Microbiologist who has accountability and responsibility, and possibly to their staff

Additionally, communicate with operators, or validation scientists, if appropriate

(e.g. for sterile operations)

Success or Failure

The results from an audit depend on the accuracy of information

A non-microbiologist should have effective access to someone who is educated in pharmaceutical microbiology

Virtual Audit with a Microbiology Auditor

Criteria to Consider for Manufacturing Audits

Excipient control – C of A, specs, QC testing, material storage, weighing

Process flow –containment, gowningProcess equipment – validation, cleaning,

sterilization, microbial monitoringProcess areas – cleaning, sanitization, access

control, gowning, gloves, microbial monitoring, ‘classification’ qualification

Source of water, water system control and monitoring

Criteria to Consider for Manufacturing Audits

Formulation – excipient and component handling, bulk material handling, in-process sampling, hold time qualifications

Dosage dependent manufacture controls (e.g. mixing, drying, milling, compaction)

Finish/fill operations – sampling, cleaning, operator technique/intervention, controls (e.g. filtration, sterilization, closure control), process qualification

Finished product QC testing, stability testing

Criteria to Consider for Laboratory Audits

Organization and reporting structure

Laboratory layout

Sample tracking, storage

Media control, made or purchased

Supplies, reagents control

Instrument control – calib., PM

Lab and instrument cleaning, disinfection

Criteria to Consider for Laboratory Audits

Lab monitoring

SOPs and their control

Microbial identification process

Exceeded limit or atypical result procedure

Quality improvement program, measures

Proficiency testing

Test methodology

Method suitability procedures

Criteria to Consider for API or ExcipientManufacture Audit

Process flow and contributing factors (e.g. intended use of compound, parenteral vs. non-sterile)

Monitoring of process

Origin and control of raw ingredients

Water system control and monitoring

Microbial monitoring of ‘product’