CHAPTER - 1

An Overview of Active Pharmaceutical Ingredient

Technology
(Bulk Drug Industry)

By:
Dr. Vijay Dhekne
General Manager
(JVAG Pharma Consultant)
 INDEX
CHAPTER -1 Overview of API, API Intermediate and fine chemicals

CHAPTER -2 Optimization of Organic reactions and processes

CHAPTER -3 Industrial Processes & Scale up Techniques

CHAPTER -4 API: Brief Overview of QA/QC

cGMP Guidelines in API manufacturing

 CHAPTER -1 Overview of API, API Intermediate & Fine Chemicals
1. INTRODUCTION:

For manufacturing any bulk drug (API) the factory building shall be so situated & shall have such
measures as to avoid risk of contamination from external. Environment involving open sewage,
drain, public lavatory or any factory which produces disagreeable or obnoxious , odor, fumes ,
excessive soot, dust, smoke ,chemical or biological emission.

1.1 Building & premises:

The building(s) used for the facility shall be designed, constructed, adapted & maintained to suit
the manufacturing operations so as to hygienic condition. They shall confirm the condition law
drawn it the factory –act 1948
The premises used for manufacturing processing, warehousing, packaging, labeling and testing
purpose shall be
a) Compatible with other drugs manufacturing operations that may be carried out in the
same or adjacent area/section
b) Adequately provided with working space to allow orderly and logical placement of
environment, materials, and movement of personnel so as to avoid mix ups between
different categories of drugs or with raw materials, intermediates and in-process material
c) Avoid the possibilities of contamination & cross contamination by providing suitable
mechanism.
d) Proper light and ventilation shall be provided and whenever required air handling unit,
A.C. units to be provided (especially in Q.C. and lab area)
e) Provided with drawing system which shall be of adequate size and so designed on
prevent back- flow and/or to prevent insects, rodents entering the premises. Open
channels shall be avoided in manufacturing area and where provided these shall be
facilitate cleaning and disinfection
f) The walls and floors of the area where manufacturing of drugs is carried out shall be free
from crakes and open joints to avoid accumulation of dust. These shall be smooth,
wastable, coved and shall permit easy and effective cleaning and disinfection. The
interior surfaces shall not show particles. A particles record of cleaning and painting of
premises shall be maintained
1.2 Water System:
There shall be validated system for treatment of water from own or any other source to render it
potable in accordance with standard specified by the authority of Indian standard or local
municipality, as the case may be so as to produce purified water confirming to pharmacopoeial
specification water shall be stored in tanks, which do not adversely affect quality of water and
ensure freedom from microbiological growth.
The tanks shall be cleaned periodically and records maintained by the Q.C. department.
Water RO system Purified Water

1.3 Disposal of Waste (ETP):

I. The disposal of sewage and effluent (solid, liquid and gas) from warm factoring unit shall
be in conformity with the requirement of environment pollution control board.
II. All the biomedical worth shall be destroyed as per the permission of the biomedical
waste rules 1946
III. Additional precaution shall be taken for the storage and disposal of rejected drugs,
records shall be maintained for all the disposal of waste
IV. Provisions shall be waste for the proper and safe storage of waste. Material awaiting for
disposal, hazardous , toxic substances and flammable designed and segregated enclosed
area in conformity with central and state legislations
2 WAREHOUSING AREA :
2.1 Adequate areas shall be designed to allow sufficient & orderly warehousing of various categories
of the materials & products like starting & packaging materials, intermediates, machine and
equipments spare parts and change items.
2.2 Warehousing areas shall be designed and adopted to ensure good storage conditions. It showed
to be clean, dry and maintained acceptable temperature limits. Whenever required special
storage conditions like temperature and humidity these shall be provided, monitored and
recorded. Proper racks, bins, platforms/pallets shall be provided of the material.
2.3 Receiving and dispatch bay shall protect materials and product from adverse weather conditions
 Raw Materials Handling Procedure
1. Receipt , Sampling, testing and Storage of Raw Materials –
Solid raw materials are received in various containers such as bags, drums, boxes etc, in
20, 25, 40/50 net weights, as specified in purchase orders and then delivered by truck.
The truck is first weighted with consignment on a truck scale before unloading to
determine the gross weight. The material is unloaded in the ‘Quarantine’ area of the
stores where a random weighing of individual containers is taken and checked with
suppliers label for accuracy of weight and label information.
The unloaded truck is then weighted for tare to determine the net weight of the raw
material consignment and compared with weights indicated on the supplier’s shipment
document. The consignment is then stored separately in the quarantine area to await
Quality Control inspection.
Incoming batch nos. will then be assigned.
2. Liquid raw material – In individual containers such as drums or carboys are received
,handled and tested in the same area and according the same procedure given for solids
raw materials
Bulk liquid materials received in 10,000 to 12,000 liter quantity by tank truck. After
determining that the supplier’s seal on the tanker is intact, the truck is weighted for gross
weight. Samples are drawn with a liquid sampler from each individual compartment a
sample is subjected to completed analysis per prescribed norms. New trucks are retained
outside the stores but inside the factory premises until the material is either approved or
rejected. On approval, the material is unloaded into storage tanks and the truck is
weighted for tare weight. The raw mixture of previously approved solvents is given an
independent batch no. the mixture is then sampled and properly analyzed. In case of QC
rejection of material, the shipment is returned to the supplier.
Gaseous raw material received in tank trunks of 1000 to 5000 kgs, shipments are
handling and tested in the same manner as bulk liquid shipments. Gases received in small
cylinders weighing 50 to 60 kg are received, sampled and tested and stored according to
the same procedure given for solid raw materials
Upon receipt and quarantine of the material, the raw materials stores dept. sends a
completed requisition slip (white copy) to the Q.C. Dept. requesting a drawing of sample
 for quality check. An authorized and approved chemist then pastes a yellow slip on each
container indicating that the material is ‘Under Analysis’. A random sampling and testing
procedures given in the section covering ‘components’. The results of testing are
reported by Q.C.D. on the Raw material analytical report. Sampling is performed

following a statistical approach generally as per the formula – + 1 , where N is the

No. of containers.
Consignments of Raw Materials that pass Q.C. testing are labeled with an “Approved” slip
over top of yellow slip on each container. Conversely raw materials that fail Quality
control testing are pasted with a red ‘Rejected’ slip on each container.
Samples of Q.C.D. slip referenced are shown as exhibit forms.
Raw material batch numbering systems:
The batch numbering system followed for all incoming raw materials can be easily
exemplified as follows:
Where,
1 – Code No. indicating raw materials for the production of API
101 – Code No. for individual raw material
90 – Year of reception
005 – Serial No. for each raw material staring with 001 every year.
3. Raw Material Distribution:
Approved raw material, are moved to the raw materials stores area and stacked lot wise
in serial order based on date of receipt. Areas are designated in the raw material stores
for each R>M> and are clearly marked with prominent signs displaying the name of each
material to eliminate product mix up
The issue of approved raw materials is strictly on a ‘First –in first Out’ basis. On Rejected
materials, the consignment is moved to the ‘Rejected Material Stores’ – for return to the
supplier.
4. Raw Material Inventory:
In order to easily account for the movement of every batch of raw materials (from the
date they are received to the final package/ amount used). Warehouse staff members
will issue an inventory card indicating the name of the product, the in house batch no.
 the amount received and when the amounts successively requested and delivered to the
production dept.
5. Packaging and labeling Materials:
They are stored in a special facility in order to keep them clean and ready for use at all
times. Packaging materials include polyethylene bags and fiber drums. Labeling materials
are conveniently stored in locked cabinets in order to allow for their proper
accountability. Records are kept at all packaging or labeling materials.
S.D.Ps to the above effects are issued by works manager and are issued by works
manager and are available in central office and each of the concerned section of
production/ stores/ QCD indicating what is stated in Drug Master files.

API – Bulk Drug

API

Large Volume/ Low cost drugs Small Volume/High cost drugs

API

Antibiotic Anti hypertensive Antidiabetic Anti Cancer Antialergic

1) Ampicillin TH 1) Nifidiprine 1) Metformin 1) Latrazole

2) Amoxycillin 2) Nitredipine 2) Anastrazole

3) Cephalexin 3) Nimodipine 3) Cisplastin

4) Cephatoxine 4) Amolodipine

5) Cephachlor
 Users of API in the form like

Tablet Capsules Syrups Injectable Ointment

FACTORS INVOLVED IN SCALING UP OF AN API:

R&D Trials:
1. Information from materials / specification of RMs
2. Flow chart
3. Reaction Scheme
4. Process Steps
5. Time cycles for each step
6. Total time cycle
7. Theoretical yield
8. Practical yield
9. Consumption coefficient after 3/5 R &D repetitive trials to fix the reaction
conditions and optimized the yield.
10. 100 gm trials for 5 batches
11. Consumption coefficient for 1 kg of the API
12. Recovery of the solvent and recycling of the solvent after checking the purity by
Gas Chromatography (GC) and Moisture Content (MC)
13. Costing of the API after recovery of the solvent
14. Flow chart preparation for bulk production 50/100kg
15. Preparation of Bulk manufacturing reactors
16. RM Specification and testing methods for each RM and solvents/ intermediates
if any
17. Preparation of specification of final API as per pharmacopeia IP/BP/EP/USP
18. Preparation of COA
19. List of polarity materials polythethylene bags/ HDFC or corrugated drums
20. Labels design given details like Name of the product with Pharma speces,
Manufacturing Date, Exp. Date, Batch no., Sealing of drums
21. Dispatch details with QC check and sample
Pharma Industry –

Bulk Drug
• Production
• QC/QA
• R&D
• Maintenance Dept.
CRO
Formulation
• Store
• Maintenance
• QC
• R&D (formulation)
• Production
• Per.
Quality management Concepts:
Quality has been defined as;
• Fitness for use
• Compliance with Specified requirement
• Freedom from defects, imperfection or contamination
• Degree of excellence
• Customer satisfaction
• Delighting customer
• The totality of characteristics of an entity that bear on its ability to satisfy stated
and implied needs
• Q = P/E
Where,
P = Performance or result
E = Customer’s expectations
Q = 1 (this is the ideal situation)
Difference between QA & QC:
Quality Control Quality Assurance
1. Produces results 1. Examine results
2. Detects deviations 2. Prevents deviation
3. Can change product quality 3. Does not change product quality
4.Concerns the operational means to fulfill 4.Aim is to generate confidence that
quality requirements requirement will be fulfilled both within the
organization & externally among customers

Role of R & D in Pharma:

Industrial R&D three major strategic objectives

1. To defined, support & expand existing business. (modifying product, use of new raw
material)
2. To drive new business (by using new technologies)
3. To broaden and deepen a company’s technological capabilities
4. The classical role of R&D is cost reduction and providing the customer support necessary
to safe guard profitability
5. A better R&D thrust in the aging phase is to renew the products or technologies of
manufacturing and drive competitors out of business, rather than be driven out.

Why R&D is required in Industry:

The necessity of R&D in Pharma industry arises from number of factors these includes:
1. Any molecules (drug) has a limited life and undergoes technological obsolescence
2. To improve safety profile of a drug. Better patient compliance and better bioavailbility
3. To fight new illnesses like AIDS
4. To comply with strict regulatory standards for approval of new drug
5. To comply with stricter environmental control standards
6. R &D costs in US are estimated at about $300 millions for each drug discovery and this is
attributed to the following:
 • Only 30 % of new drugs introduced actually generate returns to cover R &D costs
• But of 3645 new chemical entities one is active; one third of all compounds fails in
clinical trials
• Substantial financial risks are involved as a new chemical entity can fail even after
launch
• Substantial financial risks are involved as a new chemical entity can fail even after
launch.
• Increasing difficulty to find new drugs since the easy ones have already been
discovered
• Increased size and complexity of clinical trials and the need to satisfy more
demanding safety requirement
• Highly sophisticated equipments are now used for routine analysis
• Costs of clinical trials have become very high
By observing above points in India R&D is really a costly affair. We can
do R&D i.e. only development work for improvement of existing technology. R i.e.
Basic research only National laboratories or Multinational companies can afford.
Technology Transfer:
Technology in the pharmaceutical industry involves the following important the following
important aspects;
• Manufacturing aspects
• Product application aspects
• Efficiency / optimization levels
The aspects can be categorized into the following:
• Process technology –
Chemical reactions
Unit processes
Unit operations
Basic chemistry aspects
Quality Standards
• Engineering technology -
Scale up criteria
 Equipment / Machinery designs
Safety a13aspects
• System technology –
Methods
Procedures
Monitoring /control systems
Thus during ‘Technology transfer’ such as knowledge, expertise,
documentation etc. is transferred from the technology inventor to another
user. Following logical stepwise activities would arise from the user’s point.
• Adoption
• Absorption
• Adaption/digestion
• Up-gradation
• Innovation
• Technology absorption –
Means to take in the complete knowledge and expertise related to technology
aspects. The end user during technology absorption completely understands the
science and the behind the technology.
The following aspects are to be taken care:
Process and Engineering aspects
Process design/scale up criteria
Engineering aspects
Time Schedules/ Batch time cycles
Instrumentation/Control systems
Operational features in designs
Safety aspects
Do’s and Don’ts during technology transfer
• Method of Analysis –
Specification of raw materials, intermediates and finished products
Method of analysis of raw materials, intermediates and finished product
Standardization technique
• Systems –
Methods
Procedures
• Training of Personnel –
After technology transfer the user develops the art of digesting the knowledge to the
best advantage. In this user should review the following issues;
Overall material balance issues
Process optimization as an ongoing activity
Standardization of systems and procedures
Within each section/department
Between various department within the organization
Between user and external environment
Hence availability of well trained and experienced personnel is the key to technology
absorption and digestion in any organization. The necessary skills for such activities
are identified as follows:
Through knowledge of unit process
Through knowledge of unit operations
Ability appreciate and absorb “ process characteristics or chemistry
appreciation”
Expertise in instrumentation and control systems
Clarity on requirements of operating personnel in handling the process on
plant scale
Safety aspects
Knowledge and expertise in effluent treatment and disposal systems
Quality technique
• Technology Innovation –
Innovation and technology transfer can occur due to one or more of the following
breakthrough:
Totally new chemistry
New process technology
New delivery systems
 New /novel application
New/novel equipment/ Machinery systems

• Ideal Link for Professional Growth:

To create an atmosphere of affection between university and Pharma industries
Meeting the Pharma Industries to identify the areas where Univ. can work out
on specific problems to save the time of industry
Suggesting the changes in the academic syllabus from time to time to match the
pace with Pharma industry
Suggesting the practical’s which match the industrial practices simultaneously
achieving economy
Placement of students for factory training evaluating their project reports,
guiding them fir better learning techniques
Pilot plant setting, running for high value low volume
Monitoring students for higher goals and creating positive attitude, training
students for interview techniques to build the confidence gross function
activities. Marketing

Mfg. R &D

• Manufacturing :
Optimizing the plant run time
Optimization of finished product and feed stock (raw material)
Improve the economics of the process
Improve the material efficiency
• R&D :
Basic /Applied research
Efforts to modify and develop the product
Application of modified /existing into new areas
Trouble shooting problems