Lecture 13:

GLP and Introduction to

Aseptic Processing
GLP
Good Quality Control Lab Practice
QC labs do not work to GLP. In Europe GLP is concerned with safety and toxicology studies
on animals

QC labs work to Good Quality Control Laboratory Practice - GQCLP

Documentation
QC labs should follow all the principles of GDP

The following documents should always be available:

Procedures describing sampling, testing and recording data
Specifications
Procedures for the investigation of Out of Specification and Out Of Trend results
Validation records of test methods
Procedures for and records of the calibration/qualification of instruments
Procedures for the maintenance of equipment
Sampling
Sampling should be carried out according to approved written procedures
The sampling method
The equipment to be used
The amount of sample to be taken
The container to be used
Storage conditions

Samples taken should be representative of the batch

Samples should be labelled

Batch number
Sampling date
Testing
Test methods should be validated
All reagents, solutions, glassware and reference standards should all be prepared in
accordance with written procedures
Reference standards should be qualified and certified, and suitable for their intended use

Test
Methods
Warning Letters
FDA Warning Letters
Genetech Inc. 29th November 2018

Poor documentation practices

“Failure to establish and follow written procedures describing in sufficient detail the receipt, identification,
storage, handling, sampling, testing, and approval or rejection of components and drug product
containers and closures”
“Failure to prepare batch production and control records that document each significant step in the
manufacture, processing, packing, or holding of your products”
“Failure to establish and follow written procedures for production and process control designed to assure
that the drug products have the identity, strength, quality, and purity they purport or are represented to
possess”
“The manufacturing process has not been validated for your products”
“Changes to the production process for your products have not been validated”
“Failure to generate and maintain distribution records that contain the name and strength of the product
and description of the dosage form, name and address of the consignee, date and quantity shipped, and
lot or control number of the drug product”
Conclusion
Challenges of clinical development

Health authority expectations

increase over the course of clinical
development

What is good enough today will

not be good enough tomorrow

SCIENCE
VS
COMPLIANCE

Process Capability Requirements

Günter Jagschies, Karol M. Łącki,
Biopharmaceutical Processing, 2018
Topics Review

Introduction to GxP
GMP
GDP
GLP
Warning Letters
Questions?
Learning Objectives
Upon completion of this lecture, you will be able to:

1. Define what is meant by aseptic processing.

2. Explain the need for aseptic processing in biopharmaceutical fill finish processes.

3. Describe the main factors that contribute to contamination control in fill finish.
Topics

What is aseptic processing?

Contamination Control Strategy
Warning Letters
What is aseptic processing?
Sterile Product Categories
Parenteral drugs are required to be sterile.

Administration by injection (parenteral) includes the following routes:

Subcutaneous (under the skin)
Intramuscular (in a muscle)
Intravenous (in a vein)
Intrathecal (around the spinal cord)

Sterile drugs can be divided into: Pre-Clinical Clinical Phases Marketing

Drug Discovery Characterization
Studies I, II & III Authorization

Terminally Aseptically Extra care needed!

Injectable small molecules Biologics
Sterilized Prepared
Vaccines
Products Products
Aseptic Processing
When product can not be terminally sterilized, we are
required to use aseptic processing to help ensure
sterility of our drugs.

Aseptic Processing is the method of combining

individually sterilised components in an aseptic
environment, in order to maintain sterility.

It is not in itself a sterilisation process, but rather a

contamination prevention process!

Pre-sterilised product is filled in a controlled aseptic

environment.
Aseptic Processing
Dictionary definition of contamination: to pollute, to
infect, to defile by touching or mixing with, to corrupt.

To biopharmaceutical manufacturers contamination is a

physical, chemical or biological substance or residue
present in a product or area where it is not supposed to
be.

Contamination must be controlled to ensure the “safety,

quality and efficacy of sterile products”.
Microbial Contamination

Bacteria

Microbes

Fungi Viruses
Consequences of Contamination
Health Drug shortage Primary focus is on patient safety and health!
effects due due to
to unsafe manufacturing
product hold Bacteria can cause an infection in someone
who is already ill, thus making their condition
worse.
Quarantined Product Loss in
or discarded revenue for Chemicals present can cause poisoning or
Contamination other effects on the patient.
product manufacturer

Particulates can cause serious problems

Loss in such as cuts, blockages, or even death.
Loss for confidence
shareholders in the
company
Known Cases of Contamination
June 2009, Genzyme, Allston, MA
Viral ▪ Bioreactors contaminated with Vesivirus 2117.
Contamination ▪ The viral contamination came from a contaminated culture medium.
▪ Resulted in a shortage of the drugs Cerezyme and Fabrazyme. $100-300 million in lost
sales.

2012, NECC, MA
▪ Injections of methylprednisolone (anti-inflammatory steroid) contaminated with a black
Fungal mould
Contamination ▪ 76 deaths and over 800 reported cases in 20 States (2015)
▪ The root causes of the contamination included poor air quality control, poor sanitisation
practices, the use of poor quality, non-sterile and expired raw materials.

Hospira, August 2017

▪ Voluntary recall of one lot of Vancomycin HCl injection (used to treat MRSA) due to physical
Particulate glass in one vial.
Contamination Mylan Pharmaceuticals, 2015
▪ Recalled several lots of Gemcitabine (cancer) and Methotrexate (Psoriasis, Arthritis)
injectable products due to the presence of visible particulate matter.
Contamination Control Strategy
Contamination Control Strategy
Contamination control should be treated as a system with several inputs, in order to achieve the
same output – a low level of biouburden or sterility.

“A contamination control strategy should be implemented across the facility…The strategy

should consider all aspects of contamination control…to minimise the risk of contamination from
microbial and particulate sources… a series of successively linked events or measures.
These are typically assessed, controlled and monitored individually but these many sources
should be considered holistically.”

EU GMP Annex 1
Contamination Control Strategy
1st step: Eliminate the source of 2nd step: Reduce the risk of contamination!
contamination!

Facility
“A well designed, maintained, and operated
Design and Environmental
aseptic process minimizes personnel Monitoring Decontam-
Maintenance
intervention. As operator activities increase in Barrier ination
an aseptic processing operation, the risk to Systems Processes
finished product sterility also increases.”
Contamination Control
Increasing automation in the Fill Finish process in Aseptic Processing
can help to remove the operator from the Access Gowning
process, almost completely, dramatically Control and and
reducing contamination risk Visitor Behaviour
Policy Unidirectional Aseptic
Air Supply Technique

Reference: FDA Guidance “Sterile Drug Products Produced by Aseptic

Processing-Current Good Manufacturing Practice” 2004.
1. Facility Design and Maintenance
The plant should be designed and maintained to ensure it is not
itself a cause of contamination:

Monitor HVAC systems.

Correct usage and storage of equipment.
Correct usage and cleaning of cold rooms, incubators.
Maintained storage rooms / warehouses.
Clean-as-you-go policy.
Implement 6S (1-Sort, 2-Set in order, 3-Shine , 4-Standartize,
5-Sustain 6-Safety ) to avoid clutter.
Ensure the correct waste streams are used.
Alert management of any wear and tear.
2. Barrier Systems

Restricted Access Barrier System Isolator

(RABS)
3. Unidirectional Airflow
Also known as Laminar Airflow.
Clean air is supplied from a bank of HEPA filters and
passes in a unidirectional manner through the room.
Operates by “displacing” dirty air. Return air ducts
remove dirty air for exhaust.
Airflow at a velocity of 0.36 – 0.54 m/s (EU GMP
Annex 1). Number of air changes increases at higher
grades.
Used in higher classification cleanrooms or barrier
systems e.g. Grades A & B.
Airflow pattern studies (smoke studies) should be
performed to visualize airflow under dynamic
conditions.
https://en.wikipedia.org
4. Gowning & Behaviour
Many kinds of bacteria are self-motile and spread easily,
particularly in damp, humid conditions.
Fungal spores are easily dispersed in the air and in water.
But motility is not necessary! Direct and indirect transmission
by humans is the easiest way for all microbes to spread from
surface to surface and from person to person.
Basic hygiene practices, behavioral monitoring and gowning
procedures can control contamination.
Personnel Training & Qualification
Drug Discovery Characterization Pre-Clinical Clinical Phases Marketing
Studies I, II & III Authorization
Non-viable Skin flakes
Contaminants Clothing Fibres
(Particulates) Hair
Oils on Skin

On Skin
Viable
In Mucosal Membranes
Contaminants
On Hair
(Microbes)
On Clothing
5. Aseptic Technique
Aseptic technique: the procedures used to reduce contamination risk.
Extra care should be taken when working in highly-controlled environments like BSCs, LAFs,
RABS and isolators.
The design of the equipment will only go so far - good
aseptic technique on behalf of the operator is key!!
Expose product contact parts to “First Air” only – know
the source and direction of the airflow.
Avoid activities that will disrupt airflow e.g. spraying
IPA, blocking air returns.
Designate clean, working and dirty zones and plan
operations.
Sanitize gloves frequently.
Minimize entries into the critical area (buddy system).
Move slowly and deliberately – isokinetic movements.
6. Environmental Monitoring
We look at contaminants from various sources…

Air Supply Surfaces Personnel

…and we look at different contaminant types

Drug Discovery Characterization Pre-Clinical Clinical Phases Marketing
Studies I, II & III Authorization
Skin flakes, hairs, fibres, lint, Bacteria, Yeast, Moulds
Non-viable dust, particles generated by Viable
Spread from surfaces and through
Contaminants machinery Contaminants
the air, by touch transfer, aerosols,
(Particulates) Spread by movement, transfer of (Microbes)
equipment and material transfer.
equipment and personnel, AHUs.
Information Provided by EM

Is the HVAC system operating to Process Are your critical areas designed
Air Quality and controlled correctly to
standards/ specifications? Integrity
prevent contamination?

How effective are your cleaning

and sanitisation procedures? Are your operators following
Cleaning Personnel procedures correctly?
Are the cleaning agents effective?
Effectiveness Contamination Are the procedures in place
Are personnel following robust enough?
procedures?
6. Environmental Monitoring
EM Limits for cleanroom cleanliness – EU GMP Annex 1
Poll

Parenteral drugs are required to be sterile.

True

Or

False
Poll

Surfaces are a potential source of spreading

contaminants.

True

Or

False
Poll

Facility maintenance is a component of a

“Contamination Control Strategy” in aseptic processing.

True

Or

False
Warning Letters
FDA Warning Letters
No adequate EM programme in aseptic processing areas:

Taiwan Biotech Co., LTD. 31st May 2018

Our investigator identified several environmental monitoring plates from the ISO 5 (Class A)
and the surrounding ISO 8 (Class C) clean areas which exceeded action limits and for which
investigations were not initiated.
Numerous samples lacked basic documentation, including missing colony-forming unit (CFU)
counts and the identity of the person who collected the sample.
While several plates exhibited counts outside of action limits, your firm had not initiated
investigations.
Your management acknowledged that deficient environmental monitoring on these
production (areas) had been occurring for approximately 1–2 years.
https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm609829.htm
FDA Warning Letters
Poor garbing practices, poor aseptic technique:

Mylan Laboratories Limited 8/6/15

“Non-integral gloves were used…for conducting aseptic processing operations.”
“we observed an operator entering the RABS and in contact with (RABS) gloves without
sanitizing his gloved hands. These (RABS) gloves were later worn for aseptic connections,
purging filling needles, and interventions on the filling machine.”
Regulations and Reference Docs
EU Guidelines to GMP - Annex 1 – Manufacture of Sterile Medicinal Products

FDA - Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing

ISO - Cleanrooms and Associated Controlled Environments ISO 14644

PIC/S
- Recommendation on the Validation of Aseptic Processes
- Isolators Used for Aseptic Processing and Sterility Testing

PDA - Technical Report No. 13, 22, 26 and 36

EP and USP

WHO Guidelines
Topics Review

What is aseptic processing?

Contamination Control Strategy
Warning Letters
Questions?