1. PHARMACEUTICAL PROCESS ENGINEERING
REGULATORY, DESIGN AND OPERATING CONSIDERATIONS

2. REGULATORY CONSIDERATIONS

3. Companies must be able to forecast and evaluate their expenditures for new biological products.
Newly large-scale facility to manufacture a product that has yet passed in clinical trials may caused major financial loss.
Some companies use a pilot facility where the product may be manufactured at a smaller scale.
Regulatory authorities do not object to the use of pilot
production facilities for the manufacture of clinical material

4. Physico-chemical analysis of the 'final dosage form‘ correlated with a suitable bio-assay to provide assurances of product uniformity.
Bio-pharmaceutical cannot be defined by simple analyses of its physico-chemical characteristics and biological activity.
Most of the complexities occur during the bulk manufacturing process
Preparation of the final dosage form for most part is
simple.

5. Bio-pharmaceutical industry and regulatory authorities decided to focus upon the entire manufacturing process.
Validating the consistency of manufacture and characterizing the final product, constant monitoring throughout processing is also stressed.
This results in much work needing to be completed
Regulatory authorities have recently changed their procedures to eliminate the requirement for a separate establishment licence for certain 'well-defined' classes of biological products.
Enabling the authorities to allow well characterized biological products to be regulated under a single application.

6. The guiding principle
should be distinguished from facilities used in research and development that may not operate under appropriate current good manufacturing practices (cGMPs).
When manufacture of a product is transferred from a pilot to a different facility, a demonstration of product consistency, as well as data comparing the two products, together with the relevant process validation data should be submitted to the regulatory authorities.
Data generated using this protocol, as well as documentation on process validation and all stability data for the product manufactured in the new facility
For each manufacturing location, a floor diagram should be included that indicates the general production facility layout, as well as information on product, personnel, equipment, waste and air flow for production areas.
An illustration or indication of which areas are served by each air handling unit; and air pressure differentials between adjacent areas.

7. DESIGNS CONSIDERATIONS

8. The cost of building facilities that are fully validated and in compliance with cGMP can be overwhelming to biotechnology companies with limited finances.
The basic design and construction costs are driven higher by the various regulatory, containment, process utilities and waste treatment requirements.

9. Facilities Design satisfying the regulatory requirements
cost effective
allow for flexibility of operations
ensuring that the completed
facility will provide all the functions intended

10. Total project management
means integrating regulatory requirements, design and engineering, validation, as well as construction requirements on one single schedule, to determine the critical path (least time to completion).
leads to more effective management, permitting 'what if scenarios that can result in substantial savings in time and cost, especially if cost estimation is implemented early in the design phase.

11. Buildings and facilities used in the manufacture, processing, packing, or holding of bio-pharmaceuticals should be of suitable design, size, construction and location to facilitate cleaning, maintenance and proper operations.
Adequate space should be provided for the orderly placement of equipment and materials, to prevent mix-ups and contamination among different raw materials, intermediates, or the final product.

12. Facility design must be integrated in support of the process in order to comply with cGMP and other regulatory requirements such as:
flow of personnel, materials, product, equipment or glassware, and waste
flows;
product separation and/or segregation;
aseptic and/or sterile processing;
sanitary design — cleaning and decontamination and spill containment;
bio-hazard containment and/or isolation;
special clean utilities;
solvent recovery, handling, and storage;
HVAC zoning, pressurization, and filtration;
drain and exhaust systems.

13. OPERATING CONSIDERATIONS

14. 1) Implemented CGMP
GMP is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. GMP is aimed primarily at diminishing the risks inherent in any pharmaceutical production. Under GMP:
all manufacturing processes need to show capability of consistent manufacturing pharmaceutical products of required quality that comply with their specifications.
qualification and validation are performed
instructions and procedures are written in clear language, specifically applicable to the facilities provided.
operators are trained to carry out procedures correctly
the proper storage and distribution of the products minimizes any risk to their quality
a system is available to recall any batch of product from sale or supply

15. Process validation
Process Validation is a Performance Quality (PQ) of the manufacturing process. As with a PQ, the critical parameters and acceptance criteria of the process steps should be defined. The parameters can be associated with the raw materials used in the process, or with process variables (time, pressure, temperature, etc.). Process validation is associated with the process and not with the product. It is the list of instructions that is being qualified. An alternative process that produces the same product will be subjected to a separate process validation. Each functional step must be examined three times.

16. Validation strategy
1) Identifying the critical parameters and understanding how each of them can adversely affect the finished product is the first step in the validation cycle. 2) Examine the effect of each of the critical parameters on the process to ensure that the variability in the parameter anticipated during routine production does not adversely affect the quality of the product. 3) To successfully complete PV work is to examine a number of consecutive batches (usually three). The sampling and testing of these batches should be designed around the critical parameters.

17. Execution of validation field activitiesIQ
Documented evaluation of the equipment or system to establish that it has been installed in accordance with design specifications, cGMP requirements and manufacturers recommendations. OQ
Documented evaluation of the system to show that it operates as intended throughout the anticipated operating ranges. PQ
Documented evaluation of the system to show that the system operates as intended throughout the anticipated operating ranges, under conditions as close as possible to normal production.
Equipment (system) validation &
Process qualification
Installation qualification (IQ)
Operational qualification (OQ)
Performance qualification (PQ)
Process qualification
Relates directly to the changes the raw material undergoes during its transformation to the final product

18. Continue… Equipment (system) validation involves:
Sterilization validation by using temperature mapping techniques, followed by the verification of asepsis, or sterility testing
Containment validation, using the host organism/another ‘safe’ organism
Calibration of instrument and certification
Validation of computer hardware and software used in the process
Cleaning validation, particularly important in multi-product facilities

19. Prospective, concurrent and retrospective validation
Prospective validation
Covers activities that should be conducted prior to the commercial distribution of the product manufactured by either a new/substantially modified process
Concurrent validation
 involves monitoring of critical processing steps and end product testing of current production, to show that the manufacturing process is in a state of control.
Sub-set of prospective validation
Retrospective validation
May be conducted for a well-established process that has been used without significant changes
Such as changes in raw material, equipment, systems, facilities

20. Cost of validation
Validation in bio-pharmaceutical facility is based on:
the time-consuming accumulation of details
sometimes the cost of validation

21. Re-validation and change control
Re-validation necessary after any change in process or product characteristics or control procedures
Change control programme should provide for a classification procedure to evaluate changes in raw materials, manufacturing sites, scale of manufacturing, manufacturing equipment and production processes

22. Continue… MAJOR CHANGES MODERATE CHANGES MINOR CHANGES
One that could significantly affect the critical quality attributes of the product -
Unlikely to have a detectable impact on the critical attributes of the product
Have a substantial potential to have an adverse effect on the product and require submission of a supplement for approval by the regulatory authorities prior to the distribution of the product made using the change, should be justified by additional testing and if appropriate, re-validation
Have a moderate potential to adversely affect the product and require a supplementary submission to the regulatory authorities at least 30 days prior to distribution of the product made using the change
Would not shift the process in any discernible manner and might be implemented with minimal testing and revalidation

23. Major change Process- related changes
Changes relating to the manufacturing processes or analytical methods that results in changes of specification limits or modifications in potency
Scale-up requiring a larger fermenter, bioreactor or purification equipment
Changes in the composition of the final dosage form of the biological product or even of ancillary components
Extension of dating period and/or change in storage temp., container/closure composition or other conditions
Installation of a new Water for Injection (WFI) system or modifications to an existing WFI
Change of the sites at which manufacturing or other than testing, is performed
Conversion of production and relate areas from single into multiple product manufacturing areas
Major construction, or changes in location, involving or affecting environmentally controlled manufacturing or related support areas

24. Moderate changes
Automation of one/ more process steps without change in process methodology
Addition of duplicated process chain/ unit process
Addition/ reduction in number of pieces of equipment
Change in the fill volume from an approved production batch size and/ or scale
Change in responsible individuals specified in the approved application
Modification of an approved manufacturing facility or room that is not likely to have an adverse effect on safety, sterility assurance, purity or potency of product
Manufacture of an additional product in a previously approved multiple product manufacturing area using same equipment and/ or personnel
Change in the site of testing from one facility to another
Change in the structure of legal entity that would require issuance of new licenses or change on name of legal entity or location
Addition of release test
Minor change in fermentation batch size using specifications of the bulk or final product
Modifications to an existing HVAC system involving/ affecting environmentally controlled manufacturing/ related support areas but not aseptic areas, with no change in air quality

25. Minor changes
Addition of equipment for manufacturing process which identical to the primary system and serve as an alternate resource
Upgrade or minor corrective change to production air handling, water or steam supply systems using equipment of the same or similar materials of construction, design and operating parameters and not affecting established specifications
Relocation of analytical testing laboratories between areas specified in the licence
Room upgrades
Installation of non-process-related equipment or rooms
Modifications in analytical procedures with no change in basic test methodology or existing release specifications provided the change is supported by validation data
Change in the storage conditions
Change in the shipping conditions
Replacement of equipment with that identical design and operating principle
Upgrade in air quality, material or personnel flow where product specifications remain unchanged
Relocation of equipment within an approved operating room, rearrangement of the operating area or rooms where production is performed or relocation of equipment to another approved area to improved product/personnel/raw material flow and improve segregation of materials with no change in room air classification
Modifications to the pre-treatment stages of a WFI system
Change in the simple floor plan that does not affect production process or contamination precautions

26. CHANGE CONTROL PROCEDURES
May apply to :
equipment, SOPs, manufacturing instructions, environmental conditions, or any other aspect of the process or system that has an effect on its state of control
Procedure to :
prevent unauthorized modifications to a validated system
evaluate proposed changes against development and technology transfer documents;
identify and evaluate all proposed changes to assess their potential effects on the process and determine if, and to what extent, re-validation is needed;
ensure that all documents affected by changes are promptly revised;
determine the impact of changes on the critical chemical and physical attributes of the product, such as its impurity profiles, stability

27. Conclusion
Process validation represents a sizeable investment in time and resources
Identify the pitfalls normally encountered during the process of validation
To avoid time constraints that may affect the quality of work
Simple, well planned and logical approach to validation
Identify the critical conditions for each step in the process
Avoid pitfalls
Save valuable resource and effort