Spreading Knowledge is a great Legacy. MMG

1. Product Development, Regulation
and Safety
Dr. Imran Sajid
Assistant Professor
Department of Microbiology and Molecular Genetics,
University of the Punjab, Lahore-Pakistan

2. The Development of a new fermentation product depends on
various factors including:
• The market
• The Scientific knowledge
• The regulatory environment
The market is affected by the product uniqueness etc, if a market
is perceived to exist for a product this is called market pull e.g. at
the moment there is a strong market pull for anticancer, anti HIV,
drugs against dengue, ebola, swine flu etc
Scientific Push: developments in scientific knowledge some
times helps the fast development of the new products e.g.
discovery of penicillin help the establishment of antibiotics
industry in 1940s, recombinant DNA technology help to develops
modern biopharmaceuticals e.g. insulin, interferon etc
Orphan drugs: Government sponsored drugs for rare diseases in
poor countries
Development of a new product

3. Development of a new product
The Development of a new product is a long and costly process
e.g. the development of a typical new pharmaceutical product
may need
• 10-12 years to come to the market
• And may cost up to 200-300 millions USD
In drafting a proposal for the production of a new product and
throughout it development a great deal of input must come from
disciplines other than microbiology, such as
• Chemistry
• Biotechnology
• Chemical and Process engineering
• Mathematics
• Computer technology etc

4. Development of a new product
Drug Discovery
Initial Characterization
Pre-clinical trials
Regulatory approval sought to commence trials in humans
Clinical Trials (Phase I, II & III)
Submission of marketing/manufacturing authorization application
to regulatory authorities
Regulatory authorities review information and grant
marketing/manufacturing licenses
Product goes on sale
Post-marketing surveillance
Product Patenting

5. Patent Protection
Patent: An official document which gives legal right to patentee
to exclude others from the commercial use of his
discovery/invention for a specific period of time usually upto 17-
20 years
Types of Patents:
1. Product Patent: new pharmaceutical products, materials
such as bio-inscticides, recombinant proteins, devices etc are
given product patent
2. Manufacturing process patent: a new DNA isolation method,
purification of a new recombinant protein, etc
3. Method of use patent: a novel role for a product e.g mode of
bio-insecticide application, drug delivery etc
Patenting of microorganism, plants or living organisms is a bit
controversial isuue, however some time they are patented
Patent infringment
US patent, EU patent, Japanes patent, Pakistan patent

6. Product Quality and Safety
Any product that is to be released on to the market has to
conform the quality procedures
The national and international regulatory requirements must be
dealt, legal and compulsory requirements guidelines devised by
manufacturing associations must be followed
Quality assurance: The sum total of all the arrangments made
with the object of ensuring that products will be consistently
manufactured to a quality appropriate to their intended use
Quality control: quality activities employed during product
manufacturing, raw materials quality testing, in-process control,
finished product quality testing, storage etc
Good manufacturing practices (GMPs): follow the FDA guide lines
for manufacturing etc
Standard operating procedures (SOPs): validated documents for
each and every step of manufacturing process, testing, storage etc

7. There are two aspects of safety in large scale industrial
processes
1. Safety of the employees working at the manufacturing
plant
2. Environmental Safety
Manufacturing and Environmental Safety

8. Safety of the Employees/Workers
 Safety of the employees involved in manufacturing process is
a primary concern
 Workers should not be exposed to potential pathogens or
allergens or irritants e.g. dusts generated from enzyme
powder have caused allergic reactions
 Certain down stream processes such as centrifugation and
mechanical methods of cell breakage generate bioaerosols
 The GMP practices, appropriate containment and safety
equipment must eliminate the potential threats

9. Environmental Safety
 Accidental release of potentially harmful microorganisms or
microbial products from large scale fermentation processes
 Disposal of microorganisms after the fermentation
 Sometime microorganisms are deliberately released in the
environment as pesticides or for bioremediation
 Protocols must be established to ensure that there will be no
hazardous effects

10. Various agencies which regulate the overall
implementation of biosafety in industry
The overall safety is controlled by international and individual
governmental agencies
 In United states control is imposed by FDA, Environmental
Protection Agency (EPA), National Institute of Health (NIH)
 In japan: Ministry of health and Welfare
 In EU: European Commission and European Parliament,
individual states have their own regulation
 In UK: Health and Safety Executive (HSE) has major policing
role
 In Pakistan: Pak-EPA, National Biosafety Center (NBC), DRAP

11. Risk analysis
 Before any new industrial process can start operating, most
countries now require assessment risk analysis be carried out
 This is specifically required for processes using GMMs
 Risk is the function of the estimated probability that an event
will have an adverse effect and also the estimate of the
magnitude of the risk (seriousness, consequences)
 Risk analysis require both quantitative risk assessment and
risk management
 Once the risk management is implemented the process is
allowed to establish

12. Containment in fermentation process
Primary Containment
 Primary containment barriers
protect the personnel and
immediate processing facility by
preventing the escape of
microorganism from fermenter or
aerosol generated in down
stream processing
 Provided by implementing good
microbiological techniques and
use of proper safety equipments
 The problematic areas like stirrer
shaft etc are provided by two or
three seals and o rings
 All valves, seals , O rings, taps and
pumps are regularly checked
Secondary Containment
 Secondary barriers involve the
use of protective clothing, regular
medical supervision, vaccination
of laboratory and manufacturing
personnel
 Specific design criteria for
laboratories and manufacturing
plants
 Use of positive and negative air
pressure, HEPA filters, airlocks,
changing rooms for operating
personnel
 Specific protocols for the
sterilization of waste before
disposal

13. WHO classification of microorganisms on the basis of
hazard
Risk Groups Description Containment
Required
Risk Group 1 Low individual and community risk. A microorganism
that is unlikely to cause human disease or animal
disease of veterinary importance
GILSP
Risk Group 2 Moderate individual risk, limited community risk. A
pathogen that can cause human disease or animal
disease, but is unlikely to be a serious hazard to
laboratory workers, the community, livestock or the
environment, preventive measures are available e.
Salmonella food poisoning
Level 1 Containment
Risk Group 3 High individual risk, low community risk. A pathogen
that causes serious human diseases, but does not
spread from one individual to another, prophylaxis and
treatment may be available
Level 2 Containment
Risk Group 4 High individual and high community risk. A pathogen
that causes serious human or animal diseases and may
be readily transmitted from one individual to another,
no effective prophylaxis or treatmnet is available e.g
Ebola virus
Level 3 Containment

14. Process
Organism
Containment
Level
Required
Non-GMM GMM
Hazard Group
Categories
Harmless
Group I
Potentially harmful
Group II
1 2 3 4 Small
Scale
Large
Scale
Small
Scale
Large
Scale
A
Equivalent
to GILSP
A
at least primary
containment
GILSP 1 2 3 B1 B2 B3 B4
B B
Containment levels required for Non-GMM and GMM industrial
microorganisms

15. Safety facilities required for different containment level
Non-GMMs GILSP 1 2 3
GMMs B1 B2 B3 B4
Procedures
Written code of practice
Biosafety manual
Restricted access
Medical surveillance
+
-
-
-
+
+
+
+
+
+
+
+
+
+
+
+
Primary Containment
Use of closed systems for viable
microorganisms
Treatment of exhaust gases
Removal of material products, and
effluents
Penetration of the closed systems e.g.
agitator shaft, monitoring devices etc
-
-
-
-
Minimization
of release
Minimization
of release
Minimization
of release
Prevention
of release
Prevention
of release
Prevention
of release
Prevention
of release
Prevention
of release
Prevention
of release
Secondary Containment
Disinfection facility
Emergency shower facility
Airlock + compulsory shower
Decontaminated effluents
HEPA filters in air ducts
Area hermetically sealable
Controlled negative pressure
-
-
-
-
-
-
-
+
-
-
-
-
-
-
+
+
-
+
+
-
-
+
+
+
+
+
+
+