1. MANUFACTURING OF API AND INTERMEDIATES

2. Overview Introduction Scope Responsibilities The Requirements
General Considerations
Prevention of Cross-Contamination
Batch Manufacturing Records
And the others (13 items)

3. Introduction
Manufacture of active pharmaceutical ingredients (APIs) and intermediates as finished product, must follow well-defined operating principles
System and Principles must be well-defined
Manufacture must comply with current Good Manufacturing Practices (GMPs) and with the corresponding registration dossiers
GMP Compliance & Regulatory Compliance

4. 2. Scope This presentation applies to all
manufacturing sites and subcontractors,
who manufacture active pharmaceutical
ingredients and intermediates
Based on ICH Q7 (EU GMP part II)

5. 3. Responsibilities
Site Management is responsible for ensuring that adequate resources are in place to comply with the regulatory requirements
Adequate Resources to be provided
Site Quality Management is responsible for ensuring that there are systems and procedures in place for the manufacturing of APIs and Intermediates
Systems and Procedures must be in place.

6. 4. Requirements (1) General Considerations
Prevention of Cross-Contamination
Computerised Systems
Documentation
Batch Manufacturing Records
Review of Batch Manufacturing Records
Manufacturing Process
In-process Sampling and Testing
Change Control

7. 4. Requirements (2) Analytical, Biological and Microbiological Tests
Water
Recycling of Recovered Materials and
Solvents
Reprocessing
Reworking
Wastewater and Materials
Storage

8. 4. 1. General Considerations (1)
Manufacturing operations must be performed and supervised by trained and qualified personnel
Personnel must wear garments and protective clothing suited to the operation performed and taking into Account any specific Health, Safety and Environment (HSE) requirements.

9. 4. 1. General Considerations (2)
Product handling operations such as receipt, quarantining, sampling, storage, labelling, packaging and transfer must be conducted in a way to prevent any risk of cross-contamination and must be described in appropriate procedures
Specific requirements for Highly Active Substances. Dedicated and self-contained facilities must be used for these materials, e.g. beta-lactams, hormones, cytotoxics.

10. 4. 1. General Considerations (3)
All equipment, products, and containers must be clearly labelled and identified. Labels must be designed to be securely affixed, legible, and must not fade or deteriorate with time
Connections between piping (lines, flexible tubing, etc) and other manufacturing equipment used to transfer products must be controlled.

11. 4. 1. General Considerations (4)
Only authorised personnel must be allowed to enter in the manufacturing areas. Site personnel must accompany visitors within manufacturing areas
All company personnel and visitors to the site must be under controlled access and exit at all times
Visitors access and exit must be authorised and documented
Visitors must be accompanied by site personnel at all times unless training in GMPs specific to the area is provided and documented.

12. 4. 1. General Considerations (5)
Equipment used to manufacture intermediates and APIs must be qualified and uniquely identified and be part of a preventive maintenance program
Equipment, instrumentation, computerised and/or control systems, facilities and utilities used in conjunction with the above must be qualified, and systems (e.g. water systems and computerised systems) and processes must be validated and maintained in a documented state of control

13. 4. 1. General Considerations (6)
Critical measuring equipment must be in calibration and be part of a calibration program
All equipment and instruments that could have an impact on product quality, safety or efficacy must be tracked and maintained under a calibration and maintenance program
All calibrations and maintenance must be documented and the records of those activities must be archived
Calibration is essential to maintain product quality, personnel and environmental safety during operation. It is an important step for qualification.

14. 4. 1. General Considerations (7)
Starting materials, raw materials and packaging materials used to manufacture intermediates and APIs must meet predetermined specifications as defined in the registration dossiers and be released by the Quality Unit according to site procedures
All specifications developed for APIs and intermediates must contain at a minimum the following attributes: Appearance and/or Description, Identity, Assay, Impurities
Quality Unit must establish a system to release or reject raw materials, intermediates, packaging and labelling materials (ICH Q7A, under 2.2)

15. 4. 2. Prevention of Cross-Contamination (1)
Measures must be taken during manufacture to prevent/minimise any contamination risk specifically when manufacturing areas are not dedicated to a single product
Air filtration equipment and environmental zones of the finishing rooms must be subject to the requirements of the Directive “Environmental Zoning & Air Handling Systems”
Prevention of contamination. Cleaning of non-dedicated equipment used for the final steps must be validated
Environmental Zoning & Air Handling System requirements for the final steps: drying, milling, filling.

16. 4. 2. Prevention of Cross-Contamination (2)
Different batches of product or product in different phases must not be loaded or unloaded simultaneously in the same area/room
Rooms in which packaging and labelling operations are performed must be inspected immediately before use in order to ensure that all non-relevant packaging components have been removed. This operation must be reported in the batch record. (ICH Q7A, 9.44)
If operations on different products are carried out simultaneously or consecutively in the same room, the operations must be segregated and controlled.

17. 4. 3. Computerised Systems
Any computerised system which may have an impact of product quality or which deals with any GMP related data must be validated
Good Practices for Computerised Systems
Computerised Systems Validation
The scope and extend of the validation activities must be commensurate with the GxP risk and complexity of the system
Validation must be based on a documented User Requirement Specification.

18. 4. 4. Documentation
All documents related to the manufacture of intermediates and APIs (e.g. process description, batch manufacturing records), must be prepared, checked, approved and issued following written procedures.
ICH Q7, Chapter 6: Documentation and Records

19. 4. 5. Batch Manufacturing Records (1)
For each batch of intermediate or API, batch manufacturing record(s) with its associated batch number must be compiled, checked for appropriateness with the Master Batch Manufacturing record, and signed before use
Batch Manufacturing Records must include but not limited to:
Dates and when appropriate, times
Reference to each major equipment used (e.g. reactor, drier, mills, etc.)
Description of packaging and labelling materials used

20. 4. 5. Batch Manufacturing Records (2)
Batch number of the manufactured product, raw materials, starting materials, intermediates, any reprocessed, or re-worked material, and packaging materials
Any physical and chemical parameters
Critical process data
Analytical data on the finished product, if available
Sampling operations
Signature or initials of each operator who has performed a critical step and of each operator who has checked it
In-process control test results

21. 4. 5. Batch Manufacturing Records (3)
Representative(s) label(s) used to identify the finished product batch
Yields obtained at defined stages
Any deviation reported during manufacture with all relevant comments
Individual manufacturing steps must be signed
(or initialled) and dated.
A similar list is provided in ICH Q7, under 6.52
A list for Master Batch Records: under 6.41

22. 4. 6. Review of Batch Manufacturing Records
Batch manufacturing records must be reviewed and approved by Manufacturing and Quality departments according to site procedures
Any deviation, investigation, comment and any report of an Out-of-Specification (OOS) result must be an integral part of the batch record and must be reviewed before a decision is taken on the release/reject of the batch.
ICH Q7, Chapter 6.7

23. 4. 7. Manufacturing Process (1)
Critical steps and methods must be defined for each manufacturing process through a scientific rationale
Critical manufacturing steps and critical cleaning methods must be validated according to site procedures
What is the definition of “critical”?
“Critical” in this context describes a process step, process condition, test requirement or other relevant parameter or item that must be controlled within pre-determined criteria to ensure that the API meets its specification. (ICH Q7)

24. 4. 7. Manufacturing Process (2)
Critical process parameters must be identified, monitored and/or recorded/reported. They must be checked and signed (initialled) by a second person
Any deviation to critical processing and process parameters or any discrepancy in the yield range for critical steps must be documented and investigated in order to assess its potential impact on product quality.
Control all steps and parameters!
Validate the critical ones!

25. 4. 8. In-process Sampling and Testing
Sampling during manufacture and in-process control tests with defined limits when applicable, must be described in documents/procedures
Blending batches of finished products intermediate or API is allowed providing this is a condition of the registration dossiers and complies with specifications. Under this condition expiry or retest date should be based on the date of the oldest batch
Blending Batches in ICH Q7, Chapter 8.4
“Out-of-Specification batches should not be blended with other batches for the purpose of meeting specifications.”

26. 4. 9. Change Control ICH Q7, Chapter 13
Any change associated with the manufacture of active pharmaceutical ingredients or intermediates must be in compliance with the site change control procedure
ICH Q7, Chapter 13

27. 4. 10. Analytical, Biological & Microbiological Testing
Laboratory tests must be conducted on each batch of active pharmaceutical ingredient and where applicable on each batch of intermediate as described in the registration dossiers in order to confirm compliance with the approved specifications
ICH Q7, Chapter 11 (Laboratory Controls)

28. Water
*Water used in the manufacturing process must be suitable for its intended use and meet pre-defined specifications
ICH Q7, Chapter 4.3 (Water)
*We have a separate guidance document which goes into detail on Water: Type, Production, Distribution,
Use & Storage and Operations and Control of Water Systems.

29. 4. 12. Recovery of Materials & Solvents
Recovered materials and solvents must be recycled and tested to pre-defined specifications according to site procedures and in compliance with registration dossiers
Where appropriate, the number of re-cycles allowed must be defined and the recovery process should be validated.
ICH Q7, Chapter 14 (Rejection and Re-use of Materials)

30. 4. 13. Reprocessing; 4.14 Reworking
For further information refer to the guidance document entitled “Reprocessing, Reworking and Re-incorporation”.
ICH Q7, Chapter 14 (Rejection and Re-use of Materials)

31. 4. 15. Wastewater and Materials
Wastewater and materials (solids, fluids or secondary products derived from manufacture) must be discarded in a way that satisfies Health, Safety and Environmental (HSE) requirements.
ICH Q7, Chapter 4.6 (Sewage and Refuse):
“Sewage, refuse, and other waste… should be disposed of in a safe, timely, and sanitary manner. Containers and/or pipes for waste material should be clearly identified”

32. Storage
Finished products must be handled and stored in controlled/monitored areas under conditions to prevent degradation and/or contamination.
Refer to our guidance document on Warehousing and Good Distribution Practices
ICH Q7, Chapter 7.4 (Storage)
Guide to Good Storage Practices for Pharmaceuticals Annex 9, WHO Technical Report Series 908, 2003

33. Summary
It is important that you have all operations involved in the preparation of an API under appropriate control, by:
Having defined the critical process steps
Having established a robust process (PAT, QbD)
Having performed a process validation with continuing verification
Using an effective Change Control System
Investigating discrepancies, deviations; and
Learning from problems, errors and mistakes.

34. Thank You
Any Questions