MANUFACTURING OF PARENTRALS 1. Formulation and Raw Materials: Concept: The process begins with the formulation of the parenteral drug, determining its composition and concentration. Raw Materials: High-quality pharmaceutical-grade raw materials, including active pharmaceutical ingredients (APIs), excipients, and solvents, are selected based on their compatibility and purity. 2. Sterilization of Raw Materials: Concept: Due to the sterile nature of parenteral products, all raw materials, including the API and excipients, must undergo rigorous sterilization. Methods: Common sterilization methods include autoclaving, filtration, and aseptic processing to ensure aseptic conditions throughout the manufacturing process. 3. Manufacturing Process: Preparation: The formulation is prepared, and various components are weighed and measured precisely. Mixing: The ingredients are mixed under controlled conditions to achieve a homogeneous blend, ensuring uniform distribution of the API and other components. Filtration: The solution is then filtered to remove any particulate matter and ensure clarity. Filling: The sterile drug solution is filled into vials, ampoules, or other suitable containers in a controlled environment, maintaining sterility. 4. Sterilization of Final Product: Terminal Sterilization: The final product, in its container, undergoes terminal sterilization methods like autoclaving or gamma irradiation to eliminate any microbial contamination that may have occurred during the manufacturing process.

1. MANUFACTURING
REQUIREMENTS OF
PARENTRALS
BY
Dr. SRIRAM THIRUNAVUKKARASU,
Pharm.D ,

2. PARENTRAL ROUTE :

3. COMMON ROUTE OF ADMINISTRATION OF PARENTRALS :

4. WHY PARENTRALS ARE PREFERED?
1. Rapid absorption into bloodstream.
2. Predictable bioavailability.
3. Applicable in nausea/vomiting cases.
4. Ideal for emergency situations.
5. Enables precise dosage control.

5. Characteristics of Parenteral Drug Forms
• Safety (freedom from adverse toxicological concerns)
• Sterility (freedom from microbial contamination)
• Nonpyrogenic (freedom from endotoxin contamination)
• Particle-free (freedom from visible particle contamination)
{Subvisible particles no greater or equal to 10 or 25 micrometer}.
• Stability (chemical, physical, and microbial)
• Compatibility (formulation, packaging, and other diluents)
• Isotonicity (isotonic with biological fluid)

6. Parenteral Drug Manufacturing
• The parenteral drug manufacturing (Drug Product Manufacturing) process includes
compounding, mixing, filtration, filling, terminal sterilization, lyophilization, closing, and
sealing, sorting, and inspection, labeling, and final packaging for distribution.
• The manufacturing process is complicated, requiring organization and control to ensure the
product meets the quality and the specifications.
• Aseptic processing requirement adds more complication but assures that all dosage forms
manufactured are free from any contamination of microbial, endotoxin, and visible particulate
matter.
• The manufacturing process initiates with the procurement of approved raw materials (drug,
excipients, vehicles, etc.) and primary packaging materials (containers, closures, etc.) and
ends with the sterile product sealed in its dispensing package.
• To ensure the product meets required quality, each manufacturing process should be
validated to be sure that it is accomplishing what it is intended to do. For example, any
sterilization process should be validated with data showing it is killing various forms of
microorganisms.
• The validation processes are integral part of cGMP.

7. • The manufacturing facilities should be designed, constructed, and operated properly for the
production of a pharmaceutical product with the excellent quality required for safety and
effectiveness.
• Materials used in manufacturing facility must be smooth, cleanable, and impervious to
moisture and other damage.
• All connections or junctions between ceilings, walls, and floors cannot be 90 degree angles but
covered for easy cleaning.
• There should be no gaps, cracks, recesses, or other defects that can harbors for microbial
contamination.
• Air systems, lighting, and communication systems require special design to be easily
accessible without disturbing the normal air flow.
• Air pressure should be controlled so air flows from higher classifications (Grade A) to lower
classifications (Grade C).
• Doors should be self-closing and interlocked so only one door opens at a time.
Manufacturing Facilities

9. PRODUCTION AREA :
The production area is divided into 5 sections :
1. The clean up area
2. The preparation area
3. The aseptic area
4. The quarantine area
5. The finishing or packaging area

10. Flow Plan – the key in production facility design is to ensure that movement of equipment,
materials, and people is unidirectional, eliminating any crossover of clean and dirty equipment.

13. Barrier/ isolator Technologies
• Barriers/ isolators provide separation between the external clean room and a work process.
Isolator design is more dependable than barrier design.
• Barriers/ isolators are ideal for smaller facilities and much more economical from the point of
labor and maintenance, and operator costs.
• Barriers/ isolators can protect the product from human contamination as well as protect the
human from potential toxic effect of direct exposure to the drug product (cytotoxic drugs).

14. • Isolator – provide complete isolation of the inside of isolator (Class 100/ISO 5/Grade A) from
external environment (Class 10,000/ISO 7/Grade B)
• Restricted Access Barrier Systems (RABS) – provide sub-isolation protection but far better than
the laminar flow hoods. Passive RABS has its air provided by the facility (clean room) while an
active RABS has its own HVAC and HEPA system.
• RABS and isolator systems use glove ports and rapid transfer ports (RTPs).

15. Contamination Control
• Therapeutic protein products are natural nutrient sources for
microorganisms and are typically formulated at neutral pH and isotonic
that are ideal for microbial growth.
• There have been so many product recalls initiated by FDA due to
suspected microbial contamination of products.
• Sources of microbial Contamination includes:
The atmosphere – certain microorganisms like Bacillus, Clostridium, Staphylococcus, Streptococcus, and
Penicillium can tolerate dry environment and can be the source of contamination.
Water – Pseudomonas sp., Bacillus sp., and Escherichia coli are indigenous to water and are the main source of
contamination.
Raw materials – many raw materials originate from plants or animals and can be contaminated with pathogens like
E.coli and Salmonella.
Packaging – cardboard container, rubber closures, papers with moisture support the growth of mold spores
(Penicillium and Aspergillus) and bacteria (bacillus).

16. Buildings – walls, ceilings, and plasters can contain mold contamination. Floors with cracks
filled with water can also offer contamination of microbial growth.
Equipment – hard to clean locations like screw threads, agitator blades, valves, and pipe joints
can harbor microbial contaminations.
People – the largest single source of contamination. Skin, hair, moisture from breathing,
coughing, sneezing, cosmetics and clothing are sources of microbial contamination. Movement like
a simple walking can emit more than 10,000 particles per minute.

17. Controls of pyrogens – depyrogenation on glassware and equipment is maintaining a dry
heat of 250 oC for 45 minutes, 650 oC for one minute, and 180 oC for four hours.
 Heating with strong alkali or oxidizing solutions will destroy pyrogens as well.
 Thorough washing with detergent followed by thorough rinse with pyrogen free water
could make glassware and rubber stoppers pyrogen free. Water is the greatest
potential source of pyrogen contamination.
 Anion exchange resins and positively charged membrane filters can remove pyrogen
from water.
 Distillation and RO membranes are also effective depyrogenation treatments.

18. PRODUCTION FACILITIES INCLUDING
PERSONNEL:
1. Clean-up Area: The clean-up area will be constructed to withstand moisture, steam and detergents.
The ceiling, walls and floor should be constructed in such a way that the moisture will run off
quickly.
2. Preparation Area: In the preparation area, the formula is compounded. Adequate sink and counter
space must be provided in the preparation area. Cabinets should be constructed in stainless steel
materials. Ceiling walls and floor should be sealed with a vinyl or epoxy sealing material.
3. Aseptic Areai. The ceiling, walls and floor in the aseptic area should be Escaled so that they can be
easily cleaned and washed.ii. All counters should be constructed of stainless steel materials and hung
from the wall so that the dust will not accumulate.iii.All light fixtures, utility service lines and
ventilation fixtures should be recessed in the walls or ceiling to eliminate joints and o t her locations for
the accumulation of dust and dirt.iv.Any person entering an aseptic area should enter only through an
airlock.v. Environmental control of the aseptic area is possible by the development of Laminar-flow
workbenches.

19. 4. Personneli. Personnel selected to work on the preparation of a parenteral must be
healthy, neat, orderly and reliable.ii. Contamination may be possible through personnel
working on parenteral production. Therefore, they should undergo periodic medical check-
ups to ensure that they are not carriers of infections organisms.iii. They should wear
sterile uniforms, hats, masks, gloves and foot-covers. Movement within the aseptic room
(aseptic area) should be restricted, and in-and-out movement should be prohibited.iv. They
should be given periodic training regarding:a) The latest techniques adopted in the
production.a) Responsibilities of their position.b) Cleaning and disinfection procedures of
the aproduction areas, equipments and their bodies.

21. VIDEO REPRESENTATION

22. THANK YOU…