Radiopharmaceutical Production

1. Radiopharmaceutical Production Documentation STOP

2. Documentation is an integral component of GMP and the quality management system. The purpose of documentation includes the following: Defines specifications and procedures for all materials and methods of manufacture and control Ensures all personnel know what to do and when to do it Ensures that authorized persons have all information necessary for release of product Ensures documented evidence, traceability, provide records and audit trail for investigation Ensures availability of data for validation, review and statistical analysis Contents Basics of Documentation Accuracy Timeliness Legibility Completeness Permanency Reports Completed Batch Records Tables Documentation STOP

3. All documentation must be accurate, timely, legible, complete and permanent. Changes to approved SOPs are not allowed without full review and approval. Proposed changes to SOPs may be noted on Post-it notes and placed in the appropriate section of the SOP. This is a temporary measure until the proposed changes can be incorporated into a new revision of the SOP which then can be issued according to the procedure described in the SOP for Writing, Issuing and Revising Standard Operating Procedures. Marks should never be made in copies or the original of currently approved SOPs. Again, the characteristics of good documentation are that it is: Accurate Timely Legible Complete Permanent Each of these characteristics is considered in the following slides. Basics of Documentation

4. Basics of Documentation - Accuracy Accuracy • Data and information must be recorded from the instrument or equipment used without error and reflect the actual events and sequence of those events. • Hard copy records of tests from an instrument such as a TLC chromatogram must be initialed and dated by the person performing the test. • Data must be calculated properly following specified formulas and criteria and be reported without error • All comments must be initialed and dated. Comments must be in proximity to the referenced data. When cross-referencing comments, use a circled number by the data and the same-circled number by the comment. For instance, the first comment may direct to another page within the document or to an attached comments form. • A short commentary may be made by the affected data that references a second comment recorded elsewhere due to limited space. Both the first and second comment must be cross-referenced to each other by the use of the same-circles number. For instance, the first comment may direct to another page within the document or to an attached comments form. • Falsification of data is unacceptable conduct

5. Basics of Documentation - Accuracy Error Correction • Each correction made to a document must be initialed and dated by the person who made the incorrect entry if that person is available. One continuous correction may be lined out and signed and dated once per page. Separate corrections must each be initialed and dated • Correction to an already checked or verified step will require documented re-check or re-verification in the form of initials and date. • If a correction was made before its verification, then a comment must be made that the correction occurred before verification, unless already apparent based on the dates of each event • Illegible number(s) or letter(s) are treated as documentation errors and corrected according to the following steps in section 6.2.2 • Data may not be obliterated or written over in a document. Data that has been corrected must still be legible after the correction. • Data is corrected by making a single line through the data to be corrected. The corrected information is then documented and initialed and dated. A rationale for the correction (late entry, entry error, for example) must be included.

6. Basics of Documentation - Accuracy Error Correction (cont.) • When correcting data, the entire value must be crossed out and corrected. It is not permissible to correct only a portion of the recorded data. • Example: Incorrect way Correct Way 3.173.17 5 JD 15MAR2002 TE 3.57 JD 15MAR2002 TE • To document the rationale for the correction, a written reason for the change may be included or one of the following abbreviated reasons may be used for the most common error types in cases where no further explanation is required. Excluding Data • Excluded data is to be denoted by being circled and noting that the information is excluded. The reason for exclusion must be stated as a comment. Exclusions must be initialed, dated and approved by a member of the QA unit.

7. Basics of Documentation - Accuracy Error Correction (cont.) • Document abbreviation Codes • TE – transcription error. A transcription error is a recording of the incorrect data from the source to the document • CE – Calculation error. A calculation error is an arithmetic error, such as an addition mistake • DE – Documentation error. A documentation error is writing the wrong data or writing data in the wrong place. OR • EE – Error entry. A documentation error is writing the wrong data or writing data in the wrong place. (same as DE) • LE – late entry. A late entry is the documentation of information in the document after the fact. A reference should be made to the source data references in order to make the entry. • Numbers or letters may never be corrected by changing the number or letter after it has been written. NO “WRITE-OVER” IS ALLOWED. All corrections are to be made as described in this procedure • The operator who makes an incorrect entry should be the one to make the correction. • If the original chemist is not available to make corrections to an error, consult the supervisor to designate another chemist to make the correction.

8. Basics of Documentation - Accuracy Review and Verification • There are three levels of independent review of data provided in a document. These are Verified By, Checked By and Reviewed By. If required, then the document will indicate the different levels of review to be performed. • Verified by implies that a specific operation has been completed and the data have been entered correctly. • Checked by implies that a calculations have been checked and found to be correct • Reviewed by implies that the record has been reviewed for completeness and accuracy. • All calculations must be performed by one person and independently checked by a second person. A calculation check requires that the checker independently perform the calculation and obtain the same result as the operator. It is not acceptable for the checker to look at the final result on a calculator used by the operator. • The calculation performed must be completely documented in the record including the formula or equation used and the units. • All documents must be signed and dated by the person responsible for performing and by the verifier (as required) or checker (as required). The need for verification or check will be determined by the document being completed.

9. Signature Signing or initialing data indicates agreement with the legitimacy of the data content and its proper documentation (correct dates etc.). Indicate if a signature is on behalf of an unavailable person by stating “on behalf of...” or “for…” the name of the unavailable person. Signatures for continuous operations indicate that all steps in the operation have been completed as part of the single continuous operation. Both signatures and initials are acceptable. A signature or initial is not valid without a date. Dates must be handwritten at the time of signing. Signature and initials must match those recorded according to Name Signature Form (which should be part of the GMP package). Any change in name or signature will require the Name Signature Form, to be re-executed to ensure the signature and initials reflect the name or signature change. Basics of Documentation - Accuracy

10. Recording Date and Time Dates listed in the document header are required to be recorded using the following date format: DDMMMYYYY Example: January 1, 2003 would be documented as 01JAN2003. For the dates used in the batch record or any hand entries as corrections, it is allowed to use the common USA format or the European format as long as they are consistent throughout all documents. Example of the USA format: February 1, 2003 would be documented as 2/1/2003 or 02/01/2003 or 02/01/03. Example of the European format February 1, 2003 would be documented as 1/2/2003 or 01/02/2003 or 01/02/03 Notations of time of day or start and stop time are recorded military time format (24 hour clock). Examples of time format are as follows: 9:00 AM is 9:00 12:30 PM is 12:30 3:15 PM is 15:15 Basics of Documentation - Accuracy

11. Basics of Documentation- Timeliness Timeliness • All dates should be recorded to reflect the date that each entry was made on the document. It is not acceptable to use a date other than the date on which the information is being recorded (For instance, backdating). If the date the information is recorded is different from the date of the operation, both dates must be recorded in a comment so as to clearly state the sequence of events. • Data used to control a process or determine subsequent processing steps to be taken must be reported within the period of time that allows the user or receiving group to control their process. • All data that is transmitted, transferred, or utilized to control a process or determine subsequent processing steps must be supported and traceable. • Laboratories testing GMP or GLP products must document experiments and data on the same day that the activity is performed.

12. Legibility Data must be legible. Data must be clearly documented and easy to read and the meaning interpretable to the layperson with minimal assistance from the author. Handwriting must be clearly discernable. Basics of Documentation - Legibility

13. Basics of Documentation - Completeness Completeness • Data is complete when all variables reagents, conditions, and results are recorded. • Data cannot be considered complete unless the units of measure (if any) are included with the data. • All recorded data will have the signature, initials and date of the individual(s) involved in the activity. • To be complete, data must be reported in a manner that is directly comparable to the applicable specification or process control requirement without further manipulation of the data. • Repeat values must not be recorded as ditto marks or arrows within a column. All data documentation must be completed as single discrete entries. One entry per line per recordable result. • All original data including printouts, recorded values, and other original documentation must be retained, even if the data is not utilized. The original recorded information must be retained no matter where it is documented. For instance, if data is recorded on a lab wipe, the lab wipe is considered the original documentation and must be retained and treated as such.

14. Basics of Documentation - Completeness Completeness (cont.) • All attachments (that is, hardcopy printouts and charts) to a document must be labeled at minimum with equipment identification (if applicable), sample ID number, and initials with date. • No original document may be discarded or destroyed. • Affix original and/or photocopies of raw data printout(s) in the laboratory notebook or batch record with glue or tape. • In the event that one or multiple steps or procedures in a controlled document are discontinued, an explanation shall be recorded as a comment. • In the event that the batch or guidance document is not completed, an explanation to the document shall be recorded as a comment. • Define all abbreviations and acronyms • Unused space in a document is lined out using a single diagonal line that extends over the entire unused area. The unused space is marked N/A” (for “Not Applicable”) and initial and dated. • The diagonal line shall not extend into any area that has been used to record data, initials, or dates.

15. Basics of Documentation - Completeness Completeness (cont.) • If any area is inadvertently lined out, data must not be recorded in that portion of the document. Any further information must be included in the comment section. • Cross-reference information that resides in other documents (e.g., another laboratory notebook, binder, memo, technical report). Laboratory Requirements • Record all raw data such that another person with same skills could repeat the experiment or explain the action at a later time.

16. Basics of Documentation - Permanency Permanency • A permanent record is one that cannot be readily changed or altered to affect the data contained therein. It also will endure storage over time without fading, smearing or otherwise changing state. An example of a non-permanent record is a record on thermal paper. Over time and with exposure to heat, the print out will fade and or become black and illegible. • All documentation is required to be permanent in nature. If a record is not permanent, actions must be taken to ensure the record is made permanent. These actions may include photocopying and use of indelible marker. • Any hardcopy printout or chart on thermal paper must be photocopied in order to provide a permanent record. Both the photocopy and original thermal paper document must be retained and attached to the associated document • All data must be recorded in indelible ink. Ink must be blue or black (preferably blue) in color. Indelible ink is typically found in ballpoint style pens. Erasable pen is not considered an indelible ink pen. • Pencil must never be used for any documentation purposes, as it does not create a permanent record. • Whiteout, liquid paper, correction tape, or other such correction materials must never be used on any document. • Erasures must never be made on any document

17. Reports Reports give an account of the conduct of particular exercises, projects or investigations, together with results, conclusions and recommendations Where a validated process is continuously monitored and controlled, then automatically generated reports may be limited to compliance summaries and exception/ out-of-specification (OOS) data reports as required by specifications derived from process analytical technologies detailed in approved marketing authorizations.

18. Reports • There should be written reports and records of actions taken or conclusions reached, where appropriate, for the following examples (which is not an exhaustive list): • validation and qualification of processes, equipment and systems; • equipment assembly and calibration; • technology transfer • maintenance, cleaning and sanitation; • personnel matters including training in GMP and technical matters, clothing and hygiene and • verification of the effectiveness of training. • environmental monitoring; • pest control; • complaints; • recalls; • returns. • change control • investigations into deviations and non-conformances • internal quality / GMP compliance audits

19. Completed Batch Records Generation of the Batch Records • In response to an order for the product, Document Control generates the Batch Records needed for the studies. The new batch record is a printed copy of the PDF version of the Master Batch Record. Approval for the Batch Records • Document Control Person or her/his designee reviews the Batch Record printed copy to make sure there is no disagreement between the Master Batch Record and the printed copy, then stamp, sign and date the batch record on the first page to indicate the batch record is approved to use.

20. Completed Batch Records Responsibilities for Batch Record Completion • The primary and/or assistant chemists complete the batch record. A member of the QA Unit reviews the completed batch record. Each of these individuals has a distinct responsibility for assuring the quality of delivered product. All tests of the final product may be performed by either the primary chemist, or an assistant. All test results, other than sterility, should be verified by a different chemist than the one who performed the test. One chemist should verify and enter the test results into the Batch Record. Hard copies of test records (HPLC and TLC reports, for example) must be initialed and dated by the person performing the test and attached to the batch record. All entries and corrections must be carried out according to Good Documentation Practices.

21. Completed Batch Records Batch Record Review by the QA Unit • A member of the QA Unit reviews the batch record. If, for some reason, a member of the QA Unit is needed to act as a primary or assistant chemist, then he/she is not allowed to act as a member of the QA Unit for the purpose of reviewing that batch record, or for releasing that batch of radiotracer. Deviations • All deviations to the batch synthesis process must be completed and approved prior to the start of the synthesis. Out of Specification and CAPA • If there are any test results which are out of specification or if any corrective actions were required to deliver the product, then a CAPA form must be filed according to SOP QS001 on the Quality System. The CAPA form and the correct results will be attached to the batch record.

22. Completed Batch Records Batch Record Completion • Prior to use, the Batch Record should be checked to be sure it has been approved. This approval is found on page one of the batch records. After approval has been verified, the Batch Number should be recorded on every page the Batch Record. The Batch Number has the following format: MMDDYYYY-## where “M” is month, “D” is day and “Y” is year. The “##” is a 2 digit number representing the production run for that day. Reagents and Supplies • The Control number of all reagents/solutions and inventoried supplies to be used in the synthesis as specified in the Batch Record should be recorded in the Batch Record by either the primary or one of the assistant chemists. This person’s initials and the date should be entered in the “Performed By” space. The numbers should be verified by a different chemist and the initials of that individual recorded along with the date in the “Verified By” column of the Batch record.

23. Test Verification Responsibilities On each pre-release item of the batch record Quality Control Report, there is a column for Test Description, Specification, Test result, Pass (Y/N) Performed by, and Verified by. The Primary Chemist and Assistant Chemist perform all of the pre-release tests, ensure they meet the specifications and initial the Performed by Column. The tests must then be verified by a different chemist who initials the Verified by column. All test results must be attached to the batch record using SOP on Good Documentation Practices. Completed Batch Records should be retained for at least 7 years Completed Batch Records

24. Tables • Tables play an important role in GMP. There should be tables of at a minimum: • All the SOPs that are being used • All the approved corrective actions • All the training that is required and completed by each person in the facility • All the reagents and supplies required for a synthesis • A list of the approved manufacturers

25. Return to Main Menu