Documenta tion and Records

Transcription

1 Documenta tion and Records Page 1 of 30

2 Training Outcome of the Module: After completing this module, you will be able to: Recognize the importance of procedures Recognize the importance of record keeping Identify the possible consequences of not completing and certifying GMP documents Identify how to complete batch records and associated supporting documents Manufacturing instructions should clearly and accurately define each manufacturing process step. Production operators should rely upon following these approved steps of manufacture, not draft instructions. GMP rules do not allow companies to use draft, trial or out-of-date documents in commercial manufacture. The instructions, however, should be based on experience with completing the tasks. If problems arise, the procedures should be revised to reflect exactly what is required. What do the GMP rules say? Page 2 of 30

3 US FDA CFR 211 GMP Training Documentation and Records by Master production and control records. To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed... The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed. (b)master production and control records shall include: (9) Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed. International GMPs Sec 4.15 (extract) The Processing Instructions should include: a. a statement of the processing location and the principal equipment to be used; b. the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilizing); c. detailed stepwise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures); d. the instructions for any in-process controls with their limits; The need for documentation GMP regulations require that manufacturers comply with some very important manufacturing principles. One of these principles addresses the need for documentation and traceability. Regulations require manufacturers to keep many records, including records for: Raw materials Packaging materials Page 3 of 30

4 Manufacturing Quality control testing Finished product distribution Incidents and devotions Complaints Documentation allows an investigation, if required, into the manufacture of the batch. It also allows traceability to where the products were sent. GMP compliant documents A compliant documentation system should: have written procedures that are well-defined, understood and prevent misinterpretation and error be unambiguous have accurate records that provide evidence of performance allow calculations to be checked allow tracing of a batch history, in some situations, over months or years Batch records must be stored safely, and must be able to be relieved when necessary. GMP documentation and records Records are the documented history of the manufacturing process. They must be complete and accurate, and demonstrate that authorized procedures were followed (if it's not documented, it wasn't done). Page 4 of 30

5 Manufacturing documents should clearly define the manufacturing process, be easy to use, and be easy to check. They should provide a complete history of all batches manufactured. There are rules as to how GMP-compliant documents and records are handled: Standard Operating Procedures (SOPs) and Work Instructions (WIs) must be kept current and must be readily available at the worksite. All SOPs, WIs and batch processing instructions must be followed exactly. Any deviations from procedures should be reported to supervisors. Batch documents must be verified and approved before issue to manufacturing. It is the responsibility of management to provide a documentation system that conforms to the GMP requirements, and then train the users in the requirements of the system. Page 5 of 30

6 Document control Initiate new document Agree on the need Assign author/subject matter expert Consult users Prepare first draft Review draft document Review by QA, users and subject matter expert Identity document by: - Number and version - Title and review period Page 6 of 30

7 Publish new document Register document Distribute new document Train and assess competence Review and/or change document Propose a change SME, QA. user(s) assess proposal Agree on update Archive officially superseded version Retain one official copy superseded version GOOD TO KNOW - DOCUMENT RETENTION The GMP rules require that all documents relating to batch manufacture, testing and distribution must be held for at least one year past the expiry date for the batch. In practice, many companies retain these documents for longer periods in line with their legal obligations. GMP rules for control GMP requires that documents have the following control features: Title Unique number Page 7 of 30

8 Version number Date of introduction Date of review (or expiry) Signatures of at least the qualify unit and the author or subject matter expert A reference to previous document history Introducing a standard procedure All procedures that may impact product quality, that is, those procedures that would be governed by GMP, must be introduced in a formal manner. GMP rules on introducing a procedure include: Procedures must have an official introduction or "Effective on:" date. Procedures must be authorized or approved. Procedures must be accompanied by a documented training event for all users. The resulting training record must be available. Procedures must be located such that they are directly available to the users. Completed batch records must accurately reflect what actually happened during manufacture and packaging. Once the product leaves the warehouse, only the batch and test records remain as evidence of good manufacturing practice. If there is an error in the record, particularly if it relates to a formulation, should be formally investigated as soon as possible. Waiting to see if the GMP auditors find it misses the point, as it may delay recovery or correction of a significant safety problem. Page 8 of 30

9 What do the GMPs rules say? US FDA CFR Batch production and control records, (extract) Batch production and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch. These records shall include: (a) An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed; (b) Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including: (1) Dates; (2) Identity of individual major equipment and lines used; (3) Specific identification of each batch of component or in-process material used; International GMPs Chapter 4 Principles Good documentation constitutes an essential part of the quality assurance system. Clearly written documentation prevents errors from spoken communication and permits tracing of batch history. Specifications, manufacturing formulae, and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance. Specifications To ensure consistent quality of materials and product, there are written specifications for all: Starting materials Packaging materials Intermediate products Page 9 of 30

10 Finished products Specifications need to be approved by the Quantity Department, and are not to be changed without their written approval. TYPES OF SPECIFICATIONS Starting materials The requirements for starting materials must be welldefined and documented to ensure that you get the material you want, and that there are no mix-ups. Starting materials are defined by: A standard name The supplier's code A unique item code A unique lot/batch number Specifications for starting materials should include: Inspections and/or tests required Acceptance criteria Storage conditions A retest or expiry date Packaging materials The requirements for packaging materials must also be well-defined and documented. Packaging materials are defined by: A standard name Page 10 of 30

11 A unique item code, including a revision code Specifications for packaging materials should include: A detailed description of this item Inspections and/or tests required Acceptance criteria An approved label copy Intermediate product Specifications for intermediate and bulk products should be available if these are received or dispatched, or if data obtained from tests on intermediate or bulk products are used for the evaluation of the finished product. The specifications should be similar to specifications for starting materials or for finished products, as appropriate. Intermediate or bulk products that are purchased should be handled as though they were starting materials. Finished product Specifications for finished products should include or reference: An exact statement of the therapeutically active substances The product name and code (if any) The pharmaceutical dosage form Page 11 of 30

12 Physical appearance All tests and limits used to release the finished product Details of, or reference to, the test methods Sampling instructions The shelf life and storage conditions Inward goods Starting materials are purchased only from approved suppliers and to authorized specifications. Each separate material is given a Unique Identifying Number (UIN) from the Goods Received Register. The UIN and the standard name are used throughout manufacturing to identify that material and to trace its history from supplier to customer. Goods Received Register Standard Names List Status labels SOPs and Work Instructions INWARD GOODS - TYPES OF DOCUMENTATION Goods Received Register A register should be established showing the receipt of starting materials. The register should include: Date of receipt The standard name of material Page 12 of 30

13 The supplier's and the manufacturer's name for the material (if different) Manufacturer's batch or reference Total quantity and number of containers received The UIN assigned after receipt number Standard Names List A Standard Names List, as a minimum, contains: the approved supplier name for the chemical the approved manufacturer name the company item code the company standard name that is used on the Bill of Materials the grade of the material, e.g. USP, BP, EP reference to any Material Safety Data Sheets (MSDS) or safe-handling requirements A list showing the standard name for each starting material should be established. Standard names should be specific and be designed to minimize mix-ups. The standard names specified on this list should be used to label and identify starting materials during storage and manufacture. The standards names should be consistent with the master batch formula. Status labels The status of any material should be evident from the visual appearance of its status label. Status labels are required for all materials and products, including intermediates. Page 13 of 30

14 "Reject" labels should be used only for materials that are unfit for use. Those of uncertain status or destined for recovery, re-processing and the like should be designated "Held" or "Quarantine". Standard Operating Procedures (SOPs) and Work Instructions (WIs) SOPs and WIs are documents that describe how to perform a particular operation or task. They must be readily available at the worksite. You must understand them and follow them exactly for all duties you are trained to perform. Production Production documents provide evidence of the processing and quality of products. All personnel must understand the importance of these documents. Manufacturing instructions must be followed exactly, and batch records must be accurate, be complete, and recorded in real-time. Master formula and processing instructions Batch records Labels and tags Logs and forms Page 14 of 30

15 PRODUCTION - TYPES OF DOCUMENTATION Master formulas and processing instructions The master manufacturing formula provides a complete list of ingredients and their respective quantities to be used in processing. Master processing instructions describe exactly: the way in which a product is to be manufactured the sequence of processing These instructions must contain enough information to allow the company to re-create the manufacturing operation exactly as it is supposed to occur. Batch records Batch records are properly authorized copies of the master processing instructions. They provide instructions of what to do and a record of what was done, including a list of all materials and components used and the quantities used. Batch records provide evidence of the quality of our products because operators are required to sign their name to certify that the operations took place as stated. Page 15 of 30

16 Labels and tags Typical labels and tags used within the company include cleaning tags and calibration tags. These labels require (as a minimum) the date of the operation and the signature or initials of the person applying the label. Logs and forms Logs and forms, such as calibration or cleaning records, document and provide evidence that particular operations have been performed. The information you are required to enter may be a signature stating that the particular function has been successfully completed, or it may be the recording of a particular piece of information that is relevant to the manufacture of a product. Packaging Packaging documentation provides evidence that the right products have been packaged in the right container with right label, that is, the product is correctly identified. Personnel must ensure that the packaging instructions are followed exactly. Packaging Bill of Materials and Master Packaging Instructions Packaging batch records Logs and forms Page 16 of 30

17 PRODUCTION - TYPES OF DOCUMENTATION Packaging Bill of Materials and Master Packaging Instructions The Packaging Bill of Materials and Master Packaging Instructions contain all the specific information required for labeling a product. These instructions should also include areas for calculating final yield, and for calculating the reconciliation of packaging items. Packaging batch records Packaging batch records are properly authorized copies of the master packaging instructions. Packaging batch records provide instructions of what to do and are accurate records of what was actually done. They include a list of all materials and components used and the quantities used. Packaging batch records provide evidence of the product quality because operators are required to sign their name to certify that the operations took place as stated. Packaging batch records provide evidence of correct product identity. Operators are required to sign their name to certify that the operations took place in line with approved instructions, and the current revisions of the printed matter were used in the packaging operation. It is standard practice to apply one certified sample of each item of printed matter used in the packaging as part of the packaging batch record. Page 17 of 30

18 Logs and forms Logs and forms, such as calibration or cleaning records, document and provide evidence that particular operations have been performed. The information you are required to enter may be a signature stating that the particular function has been successfully completed, or it may be the recording of a particular piece of information that is relevant to the manufacture of a product. Quality Control (QC) QC records provide evidence of the quality of materials and products. Testing must be performed in accordance with methods described, or referenced, in specifications. Results of all testing are recorded and retained as part of the batch records. Test methods Test records QUALITY CONTROL - TYPES OF DOCUMENTATION Test methods Samples of starting materials, in-process goods and finished products are taken in accordance with written sampling plans and procedures. Testing is performed in accordance with the methods described or referenced in specifications. Page 18 of 30

19 Test methods contain, or reference, all the information needed to test materials and products. Test records Test records are documents that provide accurate evidence of the quality of products. As such, they are very important legal documents. The record for a test must contain all testing data, dates and signatures. It must also identify the test method and must allow all calculations to be checked. The method of recording should allow for reviews of past results and the detection of trends. Master processing instructions are probably the most critical documents in the plant. They provide the official registered, validated, company-approved instructions, and as such ensure product safety and compliance. Failure to follow the current instructions could lead to defective product, possible recalls, and harm to patients. Product manufactured not in compliance with the government-resisted details is against the law. It is never permissible to hold unofficial photocopies of master instructions for convenience. One only approved copy of the current, approved master instruction should be released each time a batch is to be prepared, because from time to time these instructions are updated to a new version. Page 19 of 30

20 What do the GMPs rules say? US FDA CFR Batch production and control records. Batch production and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch. These records shall include: (a) An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed; International GMPs Batch Processing Records 4.17 A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions. The method of preparation of such records should be designed to avoid transcription errors. The record should carry the number of the batch being manufactured. Importance of record keeping The manufacturing and testing records (along with product retention samples) are all that remain once a batch is released. These records are the only real source of information on a batch after it has been released, so they must be accurate and complete. They provide legal evidence that the company followed GMP. There are many cases where in a legal dispute, the GMP-related records are used in court to verify that the company followed GMP. They are used to investigate product complaints/adverse events. Page 20 of 30

21 Complaint investigation is a critical activity to protect patients' health. If the records are not accurate and complete, incorrect conclusions may be made about the problem. They are used to investigate trends or problems. Often, production or product history need to be checked for trends. This can only be done if the records are accurate and complete. They are always reviewed during government audits. Auditors review records to ensure they are accurate and complete and follow GMP. They place importance on this review when forming opinions on company GMP standards. Completing records Here are some simple rules for completing records: Records must be accurate. Records must be completed in real-time. Records must be legible. Records must be completed in a non water-soluble pen. Records must be stored to prevent loss or destruction. Never use whiteout or erasers. To correct data, cross out the incorrect data with one line, enter the new information, sign or initial it, and date it. Fill in all fields, even if you write "Not Applicable". Page 21 of 30

22 Changes to records Incorrect way to amend Equipment ID number CHANGES TO RECORD Correct way to amend Equipment ID number Page 22 of 30

23 Recording information in the document itself Only permanent ink, preferably blue or black, should be used to complete a document. Red ink might be used to highlight proposed changes in a document. All recorded information should be clear, legible, and accurate. Using a white correction fluid or writing over an entry to correct an error is not acceptable. If a correction is necessary, the incorrect information should be crossed out using one line. The correct information should be entered near the incorrect information accompanied by the initials of the person making the correction and the date the correction was made. If repeated information is required for several lines in a document, e.g., initials, no ditto marks ( ) or arrows ( ) should be used. Initials should be entered each time they are required. Recording data All data should be recorded directly onto the production batch record, appropriate record, logbook, form or worksheet. Errors, which are corrected based on information contained in another source document, must be referenced or the source document must be attached. Personnel who verify calculations must do so independently. Numerical data Numerical results must be reported using the same number of significant figures as required by the specification or standard. Page 23 of 30

24 Required significant digits to four places: Wrong: Wrong: 23.4 Analytical data rounding should follow the appropriate site SOP. rounding other numerical data are found below: Rules for Rules for rounding numbers For numerical data other than analytical data: If the digit to the right of the digit to be retained is less than 5, do not round up to the next higher digit. Example: 3 significant digits required Result: Round to: 23.7 If the digit to the right of the digit to be retained is 5 or greater, round up the result to the next higher digit. Example: 3 significant digits Result: Rounded: 23.8 Comments made in the Batch Records Comments made to clarify data or statements must be initialed and dated. Extended downtime during a production operation that prevents in-process checks from being performed must be noted with an explanation on the batch record, i.e., "in-process checks delayed due to shift change" or "machine down for repairs preventing in-process checks from being performed". Errors, which are corrected based on information contained in another source document, must be referenced or the source document must be attached. Reasons for problems must be explained in detail, initialed, dated and written on the corresponding pages. Page 24 of 30

25 Examples: GMP Training Documentation and Records by Writing "line down" (indicating a production line is down) on a batch sheet is not sufficient. Briefly explain the reason the line is down. Writing "problem" on a batch sheet is not sufficient. Briefly provide information that clarifies what the problem is. If a source external to the batch record is used to change data or statements, explain the source of information. Only authorized personnel are allowed to review and approve batch records. Corrections to batch records should be made by the person who made the original entry. If this is not possible (e.g., the person no longer works at the site), efforts should be made to reconstruct the data using other viable or appropriate data sources. Different sites may have different documentation rules regarding batch records. Non-applicable pages of information If a complete sheet of information on a document is not required by the process, a single diagonal line may be drawn from corner to corner. On the line N/A (Not Applicable) should be entered with the person s initials and date. If there are multiple pages that are not used, the site should have a defined procedure outlining the actions to be taken. If critical data are not recorded, a deviation report must be initiated. The deviation report form number must be included on the applicable page(s) of the batch record. Critical data include equipment readings, time, temperature, pressure, and in-process checks. If changes or corrections are necessary to the batch record, they must be explained and approved by quality. Formal documentation, i.e., a memo or signed change request form, must be kept for each change. Types of documentation systems that are audited Documentation systems that should be routinely audited are: Equipment assembly, cleaning and use log. Page 25 of 30

26 Component, drug product container, closure, and labeling records. Master production and control records. Batch production and control records. Production record review. Laboratory record systems including electronic data systems and analytical methods. Distribution records. Annual Product Reviews Complaint files. Validation and qualification systems of processes and equipment. Equipment calibration and maintenance records. Environmental monitoring records. Training records. Components of documentation systems All documentation systems should have approved and established SOPs that govern how the particular documentation system is managed. The topics that should be included, at a minimum are: Document control and distribution. Approving bodies and date of approval. Timeline for review and revision. A tracking and follow-up method. Assurance of training regarding documentation. A description of the purpose of the system. Storage and retrieval information. Page 26 of 30

27 Directions for handling atypical occurrences within the system. Documentation may consist of logbooks, worksheets, electronic data, highly controlled paper documents, equipment readout or charts. Revision of documents GMP document revisions should be properly controlled through a formal revision system as part of the document management system. Documents should be approved, signed and dated by appropriate and authorized persons, as defined in procedures approved by Quality Assurance. As part of the document management system there should be a method in place to assure that GMP documents are revised regularly to comply with the GMP requirement that states that all documents should be complete and accurate. When revised documents are issued, there should be a method in place to promptly remove superseded revisions from the area. Only official records and procedures should be used by personnel. If approved documents (e.g., validation reports, released batch records, etc.) need to be amended, only appropriate personnel who have proper authorization may amend the documents. There should be a system in place to manage proposed amendments to approved documents. Retention of documents The site should have a record retention schedule for different types of documents. All records associated with a manufacturing lot should be retained for a minimum of one year after the drug product expiration date. Validation records or other records that are not specific to batches or lots may have to be retained longer. Records may be retained as original copies or true copies, e.g. microfilm, scanned copies, etc. Documents may be stored off site but must be easily retrievable. Original raw data of manufacturing and the laboratory should be retained according to site procedures. Page 27 of 30

28 Electronic data If data is recorded in electronic systems, detailed procedures relating to the system in use should be available and the accuracy of the records should be checked. Only authorized persons should be able to enter or modify data in the computer and there should be a record of changes and deletions; access should be restricted by passwords or other means and the result of entry of critical data should be independently checked. Batch records and other critical documents electronically stored should be protected by back-up transfer on magnetic tape, microfilm, paper or other means. It is particularly important that the data are readily available throughout the period of retention. Page 28 of 30

29 Summary A good documentation system is the cornerstone of a GMP compliance system. All personnel must follow the written and approved documents in the day-today operation of the manufacturing facility. It is the responsibility of management to provide a documentation system that conforms to the GMP requirements, and then train the users in the requirements of the system. It is your responsibility to understand the documents and use them correctly. When you sign or initial a record saying that you carried out a process, you are certifying that the process was carried out according to the written and approved procedures. When you sign or initial a checking step in a record, you are saying that you observed what was done, and can verify that it was done correctly. It is only by having a documentation system that everyone complies with, that we can demonstrate that we have manufactured a quality product. Page 29 of 30

30 TAKE THE TEST NOW Number of questions: 10 No time limit Allow you save and finish at a later date Allow you to go back and change your answer Attempting each question is mandatory Pass mark at and above 70% Print results and certificates Page 30 of 30