Radiopharmaceutical Production

1. Radiopharmaceutical Production Validation Master Plan STOP

2. The Validation Master Plan (VMP) is an extremely important document because in constructing it, many serious commitments and decisions have to be made. The VMP is a document that documents the way the company will operate, who has control over the various aspects of the validation activities, and how production, quality control, and personnel management will be directed. Contents Validation in General Validation Policy Validation Master Plans Content of the VMP Validation Plans VMP Summary Literature and Example Validation Master Plan STOP

3. Validation in General The process of validation starts with the construction (or renovation) of the facility to be in compliance with GMP guidelines. These processes should be outlined in a Validation Master Plan (VMP). The VMP should include: • Water (generation, receipt, and distribution) • Heating, ventilation, and air conditioning (HVAC) • Terminal sterilization of product (either by autoclave or filter sterilization) • Compressed air (generation and distribution) • Premises (to be sure they meet all GMP practices – see the section on Facilities) • QC laboratories (analytical and microbiological) • Production and control operations involved in the manufacture of radiopharmaceuticals. Validation continues with validation plans for individual processes and equipment. These include: • The development of validation SOPs • The development of process SOPs • Testing of the production process • Development of analytical methods • Validation of the process • Revalidation of the process whenever there is a change in the procedure or new or repaired equipment is used. • A summary table is given on the next page

4. Validation in General Summary Table for Validation

5. Validation Policy • Qualification and validation should not be considered as once in a lifetime exercises. An on-going programme should follow their first implementation (continuous improvement) and should be based on at least an annual review. • The commitment to maintain continued validation status should be stated in the relevant company documentation, such as the Validation Master Plan. • The responsibility of performing validation should be clearly defined. A schedule of validation activities is an excellent way to be sure that all processes and equipment stays in validation. This schedule should be signed off when the tasks are completed and this document kept as a record of completion. • If possible, all the validation procedures should be scheduled for a specific time such as the first working Monday of the quarter or year. This way all the continuing validation procedures can be accomplished at the same time and it makes it easier to remember to do them all.

6. Validation master plans More Site Master File • The VMP should be a concise and easy-to-read document which will serve as a guide to the personnel who are responsible for performing validation. According to the WHO • The Validation Master Plan (VMP) complements the producer’s site master file and should be the first document to be reviewed during inspection by a regulatory authority. • To learn more about the site master file • The VMP reinforces the commitment of the facility to GMP. The Functions of the Master plan should be: • Education of management • Project monitoring and management • Project training • Audit of the validation program • Update of regulatory agency requirements

7. System Description. Validation Approach. Site Activities. Documentation and Procedures. Scope of Documentation. Validation Schedule of Activities. Project Master Schedule. References Glossary. Components of a typical VMP Introduction. Plan Origin and Approval. Derivation. Scope of Validation Activities. Validation Objectives. Validation Plan Review. Roles and Responsibilities. An Overview of Activities. Division of Responsibilities. System Description. Overview of System. Overview of Process.

8. Content of VMP Particular Attention should be paid to the following areas within the VMP • Production and QC premises, including controlled environments • Process and QC equipment, including location • Pharmaceutical air (HVAC) and water systems • All potentially critical utilities (such ascompressed air, steam and cooling liquids, and so on) • Computer control systems • Manufacturing processes • List of validation protocols, including format • List of relevant SOPs • Product specifications including prospective (and tentative) IPC acceptance criteria • QC and IPC methods, validation, if applicable • Reasonable unexpected events Some Advice on the content of the VMP from PIC/S can be found by following the arrow More VMP Recommendations

9. Validation plan • A validation plan describes the overall philosophy, intention and approach to establishing that facility performance is adequate (validation policy). • It should identify: • the responsible persons • what should be validated, • where the validation should be done, • when validation should be performed, and • why and how the validation should be performed. • It should include a breakdown of the process into separate parts. It should also determine which processes are critical to the quality of the product and therefore require validation. • For example, in a project to commission an FDG production process, the operation of the synthesizer is critical and will require IQ, OQ and PQ; and the operation of the laminar flow hood is critical and will require IQ, OQ and PQ.

10. Types of Validation Plans A new validation plan should be developed whenever these situations arise: • Construction of new premises • Major renovation or additions to existing premises • First time validation of previously unvalidated processes or unit operations • Automation or computerized implementations of processes • Installation of new equipment Basic questions to be answered • What will be validated? • Who is responsible for the validation tasks? • How will the equipment be qualified and the processes validated? • How will the validation be documented? • What are the criteria by which a successful validation will be evaluated?

11. VMP Summary Target all personnel involved in the validation when creating the master plan. Keep the VMPshort, but provide enough information so that the document isfunctional. Provide for flexibility to deal with changes, but do not avoidmaking the required decisions early on in the project. The life cycle mandates that the validation process becomes an ongoing project, which requires constant attention.

12. Literature and Example More Example VMP - long More Example VMP - short More General GMP Information More VMP Recommendations An example Validation Master Plan can be found HERE Sample of a Simple Validation Master Plan Literature on Validation Master plans and the Validation Process can be found in the references to GMP. The major references and some presentations on GMP are available by following the MORE arrow. More information specifically on Validation Master Plans can be found by following this arrow

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