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					Documentation Procedures
INTRODUCTION The purpose of this monograph is to provide guidance on the documentation requirements for the successful manufacture and control of medical products. It is envisaged that the monograph will be a useful reference work for those personnel preparing documents, using documents and training staff in the usage of documents. The monograph is not, except indirectly concerned with matters such as health and safety and the environment. Documentation is also important in research and development and in particular during the registration of a new product but this is considered a subject an itself and is not covered in this monograph. Types of Pharmaceutical Documentation Five basic types of documents will be described in the monograph, and key requirements for each will be outlined. Policy documents give the company overview of what will be done, who is accountable for ensuring it is done and company organization to aid continuing with policy. Specifications are documents which describe starting materials, packaging materials, intermediate, bulk of finished products in terms of their chemical, physical and when appropriate biological characteristics. A specification normally includes descriptive clauses and numerical clauses, which define standards and permitted tolerances. Procedures are formal written instructions, which detail how an operation is to be performed. They are required for all operations, which can affect the safety, identify, strength, quality and purity standards of medicinal products. Such documents are often termed SOPs or Standard Operating Procedures. Work Instructions are batch-related documents, which list all the starting materials to be used and the production operations. Records are completed documents, reports, instructions, and protocols, logbooks, log sheet etc. that are used to record information. They provide a history of each batch of product together with data pertaining to the quality of this final product. Documentation described above may be stored and handled electronically. Reasons for Documentation Consistent Control over the Operation Documentation communicates information concerning a wide range of activities carried out during pharmaceutical manufacture and control operations, providing detailed and clear instructions. Written statements, whether on hard copy or generated electronically and viewed on a screen avoid the risk of misinterpretation inherent in oral communication.

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Consistent Training Documentation serves as a useful training aid. Clearly written documents are a prerequisite of effective training procedures. They help to ensure that personnel required to undertake a new task are provided with the necessary information on how the task is successfully completed. Regulatory Requirement Regulations for the manufacture of medical products call for a detailed documentation system to be in place. (For example refer to Chapter 4 of Volume IV GMP for Medicinal Products. The Rules Governing Medicinal Products in the European Community 1992). Permanent Traceable Record Records enable information to be recorded clearly and unambiguously in order to document what actually happened during a pharmaceutical operation and not just the actions, which were intended by the approved procedure. Accurate recording of observed values and events is essential in order to maintain an ‘audit trail’ which allows for subsequent investigation and tracking of batch history. Control of Deviation and Change Deviations from or planned changes to the operation must be recorded, reviewed and authorized to ensure that they do not have an adverse effect on the quality, safety or efficacy of the product. GENERAL PRINCIPLES 1. A Standard Operating Procedure should be written to define the format of all types of site documentation. 2. Documents should have unambiguous content and follow a logical sequence and common design. document:  The method by which the documents are to be reproduced to ensure a clear and legible copy.  The proposed use of the document to provide or to record information  Location of information for efficient usage.  The size, shape and layout to ensure that there is sufficient space to record information clearly and to be compatible with filing facilities. 3. Documents should include the following elements:  The name of the company and site  A title (written so as to enable easy indexing)  A reference and revision number  Record of circulation (e.g. copy number)  Reason for revision
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The following should be considered before preparing a new

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 Signatures of the people who have written and authorized the document.  Period of validity (expiry) 4. Use language that the users can understand and an agreed system of units of measures. Do not make it too long or include repetitive statements or data. Avoid abbreviations, which are not generally approved. 5. Ensure that the personnel who will use the document are involved with its initial drafting. Where possible, such personnel should provide the draft. CONTROL OF DOCUMENTATION 1. Introduction: It is critical to any pharmaceutical manufacturing activity that there are clearly defined, written procedures for controlling the preparation, approval, issue, updating and change of all documentation. The procedures should also ensure that only current, approved documentation could be issued or used. All completed records should be securely achieved but still available for inspection or review should be need arise. Control of documentation may be the responsibilities of one department if not care must be taken to ensure consistency. 2. Document Preparation: The preparation of documents is best done by those involved in and who are familiar with the processes or procedures. There should be a guide to the preparation of all types of documentation in the form of Standard Operating Procedures, containing details of the sources of information required to prepare the particular documentation. The guide should also provide guidance on for example, style or format of documentation. Preparation of documentation should be done using means, which minimize the risks of reprocessing and rechecking. 3. Indexing and Numbering Master documents should be indexed and this may be done in a number of ways. Editions (versions) of documentation should be differentiated; it is best to use a numbering system. A computer database is a suitable means of storing the series of numbers because update and review is then easy and rapid. The numbering system should embrace documentation for all company activities which have an influence on Good Manufacturing Practice, for example SOPs, manufacturing and packaging documents, quality control specifications and methods, sampling procedures and record sheets.

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For example, SOPs could be 001 to 999; Manufacturing Documentation could be 1000 to 1999 etc. Further sub-division is then possible. For example, SOPs may be divided by department. Quality control specifications and sampling procedures may be divided into starting materials, intermediates or packaging components etc. 4. Approval of Documentation All documentation should be approved in authorized persons from appropriate departments. The level of authority of the approvers will depend on the document in question and the scope of their approval must be defined in a procedure. Where contract work is carried out for a third party, a responsible person in the contract-givers company should also approve the documentation. 5. Distribution and Control of Copies Copies of procedures should be available in the relevant departments but there should be no unauthorized copies. This enables reviewed or update documents to be issued and superseded ones to be withdrawn in an orderly fashion. It also prevents the use of out of date documents. To this end there should be a method of authenticating official copies and maintaining a list of recipients and return dates. Batch-related documentation e.g. manufacturing or packaging instruction are commonly produced by photocopying a master document or by computer generation from a database for each batch to be produced. 6. Documentation Review There should be a review mechanism for regular updating of all procedures. The review should be carried out by those who are directly involved in the use of procedures. Batch-related documentation should be reviewed frequently taking into account data and experience gained since the last review, bearing in mind the implications of any proposed change on the regulatory status of the process in all markets. All changes should be approved by the quality and production department a dif appropriates the regulatory affairs department. Specification review should take into account data, experience and such issues as changes in regulatory requirements or changes in the official monograph for the product. Changes should be approved by the quality department and if appropriate the regulatory affairs department. 7. Organization One department should have control of documentation issue and archiving. Whilst control rests with the appointed department much of the pharmaceutical documentation will be written by the department, which ultimately uses it.
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8. Storage and Archiving Storage of documentation may be achieved using hard copy, magnetic disc, microfilm or microfiche, or optical disc. As a precaution against loss of stored documentation, duplicate copies should be made and kept in a separate location. Caution is necessary when new technology is being utilized to ensure that is not connected or so. Copies of all editions (versions) of master documents should be stored for five years from being superseded, although product liability law and health and safety considerations may call for longer storage. This may be achieved by storing hard copy, microchem / microfilm or by electronic means. Batch related documentation should be stored for at least six years beyond the manufacturer date of the batch. Samples of raw materials and of product both a bulk and as packed product also constitute part of the batch records and should be retained for a similar period as do associated chart record and print-outs which may be stored separately. RECORD COMPLETION Documentation Entries Persons making entries on documents should use clear, legible writing confirm the entry with initials or signature and where appropriate the date. Entries should be made in ink or other permanent medium. Positive entries should be made and ticks or ditto marks avoided. Errors should be corrected such that the original entry is not lost and the correction signed and dated. Where appropriate the reason for the change should be added. Correction fluids must not be used. If a page becomes illegible or otherwise unacceptable add a new page and retain and endorse the original to this effect. Further guidance on computer and electronic documentation is detailed in Section 6. KEY DOCUMENTAS The content of major documents is defined but some of these details may also be found in other documents. 1. Quality Manual a. Quality Statement and Quality Policy The Quality Manual should contain a clear statement of the company’s policy on and commitment to quality, signed by appropriate senior managers and / or directors. The manual should include a statement that commits the company to providing products, which are safe and fit for the purpose for which they are intended. Also a
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statement should be included which defines the means by which the company plans to achieve this end such as a quality system, training etc. Those signing should by signing the policy, affirm that it is their responsibility to ensure that conditions prevail which will allow this policy to be fulfilled. b. Contents of the Quality Manual In addition to ‘a’ the quality manual will contain sections on all aspects of pharmaceutical GMP. The level of detail required will vary depending on how the company has set up its documentation system, but it is not normally useful to repeat or include all the information that would appear in company procedures. Frequently the quality manual covers broad policy and particularly if the company is multisite, can be used to assist each site develop its procedures to be consistent with a corporate policy. 2. Site Master File A Site Master File (SMF) is a prerequisite for inspection of UK pharmaceutical manufacturing sites where recognition under the Pharmaceutical Inspection Convention (PIC) is required. There are similarities to the type 1 DMF which may be produced by companies with products for the USA. Detailed guidelines have been published in the UK by the Medicines Control Agency. The SMF should include the following:  Brief information on the company and its site.  Licensable activities carried out by the company.  Other activities on the site.  The company name, address, telephone and facsimile numbers together with details of contact during and outside normal working hours.  Type of product manufactured on the site and use of contractors for any operations. More specific details are required on personnel, equipment and storage systems. 3. a. Receipt Procedures A SOP should be in place to describe the receipt of materials onto site. The procedure should describe the following elements:  Initial inspection on the delivery against the delivery note, which should cover verification on the supplier’s labels and the integrity of the consignment.  Verification against the company purchase order to ensure that the correct material and the correct quality have been received from an approved supplier in the correct packaging.

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 Confirmation of the number of supplier batches in the delivery as each batch should be considered as a separate internal batch.  The generation of company receipt records (i.e. Goods inward Document) and the allocation of internal batch numbers.  Preparation of the container identity labels which should specify the designated company approved name, internal code reference, receipt batch number or bar code, material status (e.g. quarantine) and retest or expiry date.  Non-compliance c. Records The extent of labeling and receipt documentation required will depend on whether computerized storage is used, although the same information will have to be recorded, albeit electronically. 4. Sampling The selection of samples of all stages of manufacture from the receipt of raw materials and components into stores through to bulk intermediates and packed stock, should be described in a SOP. Since the results obtained by testing samples determine whether a batch or delivery is accepted or not it is essential that clear instructions are given to the sampler to ensure that representative samples are taken. a. Procedure The sampling SOP should include the following elements:  Who is responsible for sampling?  How to access the appropriate sampling plan; the plan should specify the size of the sample required or indicate how this is to be calculated according to the batch / delivery size, the number of containers to be sampled, how many samples are required and their destination.  Safety precautions to protect the sampler and product emphasizing that only one batch should be sampled at any one time.  The techniques and equipment required for sampling, including sterile methods where appropriate.  The external checks and inspections which should be performed prior to sampling, i.e. verification of material and batch codes or bar codes, conditions of containers, condition and appearance of material a checklist which can be completed by the sampler may be considered of value. reporting to ensure materials received damaged. Contaminated or incorrectly supplied are appropriately sentenced.

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 Non-compliance reporting; this should detail how material which does not meet the samplers acceptance criteria is identified and sentenced.  Sample containers to be used and their labeling.  Identification of original containers, which have been sampled.  Cleaning and storage of sampling equipment.  The need to re-secure original containers after sampling taking care not to contaminate the material. b. Records The extent to which records are kept at the sampling stage will depend on the responsibilities assigned to the sampler to undertake a receipt inspection of the container and contents. However as a minimum a record should be made of all external checks and inspection performed before and during sampling. 5. Specification Specifications for materials and products are an essential element of the quality system. They form the definitive in-house standard to which products are released in the confidence that the regulatory requirements are met by materials purchased, products manufactured and that they both continue to comply during their shelf life. They are established on the basis of patient safety, material or product performance and process capability and define the tolerance, which should be met. Specifications should be in writing have an issue date and be approved by the quality department. a. They should be updated as required bearing in mind that licensing approval in all markets may be needed prior to implementation of any change. Starting and Packaging Materials Specification Specification for starting and packaging materials (refer to Appendix 4 for an example of a document) should include the following elements:  Description of the material.  Designated name with company code reference.  Names of approved producers and suppliers.  Specimen of printed materials.  Sampling and testing, including retest requirements and shelf life.  Qualitative and quantitative requirements with acceptance limits.  Storage conditions.  Special precautions.  Details of any factorization procedure if applicable.  Requirements for reference samples.  Drawings with dimensions.
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b. Intermediate and Bulk Product Specifications Specifications should be written for intermediate and bulk products if they are to be purchased or despatched or if data obtained from intermediate products are sued for the evaluation of the finished product. They should include the following elements:  Description of the material.  Designated name with company code reference.  Names of approved producers and suppliers.  Specimen of printed materials.  Sampling and testing, including retest requirements and shelf life.  Qualitative and quantitative requirements with acceptance limits.  Storage conditions.  Special precautions.  Details of any factorization procedure if applicable.  Requirements for reference samples. c. Finished Product Specifications Specifications for finished products should include the following elements:  Designated name with company code reference.  Description of the material.  Names of approved producers and suppliers.  Specimen of printed materials.  Sampling and testing, including retest requirements and shelf life.  Qualitative and quantitative requirements with acceptance limits.  Storage conditions.  Special precautions.  Details of any factorization procedure if applicable.  Requirements for reference samples. d. Purchasing Specification The purchasing specification should be agreed with the supplier and include the following elements:  Designated supplier and company name of the material.  Supplier and company code references.  A set of physical, chemical and if applicable, microbiological parameters with limits and the test methods to be used.  Sampling plans, quality levels and acceptance / rejection criteria.  The method to be used for packaging the material e.g., container type, quantity per container, number of containers per pallet and labeling requirements.
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 Special conditions, if applicable for transport and storage.  The documentation requirements of the purchaser, which may include safety information documents and certificates of analysis or conformity. e. Analytical Documents Results of analysis and testing of all starting materials, intermediates, bulk and finished products should be recorded. i. There is also a requirement for a policy and / or procedure to define retesting and investigation of out of specification results. Starting Materials Testing Records The testing of each material to be used for pharmaceutical manufacture should be recorded. The record should include:  Date of receipt.  Name of material, (in-house name).  The batch number.  The results of all tests carried out, including those obtained from a suppliers certificate of analysis, which should be identified as such.  Identity of the person who carried out the tests.  A signed decision by the quality department as to the status of the material e.g. released, rejected or other status.  Where potency is known to be variable, a clear statement of the value.  Data of status decision, and status review date or expiry date of material. ii. Packaging Components Testing Records The testing of each packaging component should be recorded the record should include:  Date of receipt.  Date of testing.  Name of component, (in-house name).  Batch number.  Results of all tests carried out, including those provided by the supplier.  Identify of the person who carried out the tests.  A signed decision by the quality department to the status of the component, released, rejected or other status. iii. Intermediate, Bulk and Finished Product Testing Records Records for these should include:  Date of manufacture of the stage.  Date of sampling and of testing.  Batch number.  Name of the product (in-house name)
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 Tests carried out and results.  Identity of person who carried out tests.  Signed decision by the quality department as to the status of the material, released, rejected or other status. f. Manufacturing Documents Each product, process and batch size should have a Manufacturing Formula and Process Instruction, which are often combined into one document. Each product, type and pack size should have a Packaging Instruction. Formulate and instructions should be up-todate and be formally authorized by the quality department, production, and other technical staff as detailed in the operating procedure. Each batch or part batch processed or packaged should have a Batch Processing Record or a Batch Packaging Record. These records should be based on the relevant parts of the formula and instructions. The records should be prepared in such a way as to avoid transcription errors. Records with signatures should be completed during processing and not retrospectively. Batch records must require the recording of actual value obtained rather than just a signature confirming that readings were within specified ranges. Batch records should be stored in such a manner to enable them to be rapidly retrieved and should have sufficient information to give the history of the batch and all relevant data pertinent to the quality of the final product. g. Manufacturing Formula: Manufacturing Formula should include the following elements:  Product name and product reference code.  Pharmaceutical presentation (e.g. syrup, cream), product strength and batch size.  A list of all starting materials to be used which should be described using a designated name and a company code reference, which is unique to the material and its grade.  The quantity of each starting material to be used.  Details of any factorization procedure or calculation to determine the required quantity should be included.  Quantities should be stated in a uniform system of measurement.  Materials of variable potency should have a statement of acceptable limits and potency; in the case of an average being required limits should also be defined.  The expected final yield and critical intermediate yield with acceptable limits.

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 Materials that are added but not included in the final product should also be listed e.g. a gas used to purge a solution. h. Process instructions: Process Instructions should include the following elements:  The location of the process.  Major equipment utilized.  Reference to procedures explaining how equipment is cleaned, assembled, calibrated, sterilized and checked.  Detailed stepwise process instructions including material checks the order for adding materials, critical process checks such as mixing times, temperature checks, pH checks and moisture checks reference may be made to standard operating procedure which give detailed instructions of how operations are performed.  Critical in-process parameters with their limits and guidance on action to be taken to bring the process within these limits.  Bulk storage conditions, which should include any special environmental conditions, labeling requirements and type of containers to be used.  Special precautions. i. Batch Processing Records Batch Processing Records or Batch Manufacturing Records should include the following elements:  Product name and product reference code.  Batch number.  Batch size.  Check signature for correct issue documentation.  Dates and times of each critical operation, including starting and completion time and date.  The names of persons responsible for each production stage.  A recorded check before and after processing of the batch that equipment / work area clearance has been completed to ensure all materials and documentation form a previous process operation have been removed.  Batch number(s) and / or analytical number(s) and quantities of each starting material actually weighed and added to the batch; details of any reworked materials should also be listed.  Signature or initials of operator on completion of significant stages of production and for critical stages such as weighing and checking correct material identify the
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signature of the person checking the operating; electronic verification such as bar coding or electronic weighing system may remove the need for this check.  Major equipment utilized with details of its preparation, cleaning and sterilization as appropriate; this information can be recorded in an equipment log, including a reference to the previous material processed.  Record of all relevant processing steps.  Recorded values of all in-process control and initials of the persons completing them.  Final product yield, and critical intermediates; all calculations should be recorded on the document and yields outside the predefined limits should be investigated and the results reported.  Record of storage conditions in bulk.  Records of any problems and details of any deviations from the manufacturing formula or process instruction; these should be authorized by production, quality department and other technical staff as detailed in the production deviation procedure.  Data of quality department and / or production approval for next stage of production. j. Packaging Instructions Packaging Instructions should include the following elements:  Product name and pack reference code.  Pharmaceutical presentation, product strength and the pack size detailing number, weight or volume of product in the final container and the number of containers in the collated pack.  Major equipment utilized.  List of all packaging materials to be used, using a designated name and a company code reference, which is unique to each material.  Quality of each packaging material to be used.  Expected yield and critical intermediate yields with acceptable limits.  Overprinting instructions for each component, including batch number, manufacturing date and expiry date.  Detailed step-wise packaging instructions including line clearance checks before and after packaging to ensure all materials from previous packaging have been removed and details of any subsidiary operations such as batching of labels; reference of SOPs may be made which will give detailed instructions of how operations are performed.
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 Critical in-process parameters with their limits and means of control.  Special precautions. K. Packaging Records: Packaging Records or Batch Packaging Records should include the following elements:  Product name and pack reference code.  Batch number of bulk product.  Batch numbers of all products contact or printed packaging components.  Quantity of bulk product to be packed.  Batch number of packed finished product.  Quantity of packed finished product.  Check signature for the correct issue of documentation.  Dates and times of each critical packaging operation which should include starting and completion dates.  Names of persons responsible for each packaging operation.  A recorded check before and after packaging of the batch that a line / area clearance has been completed to ensure all materials and documentation from previous packaging operations have been removed.  Signature or initials of an operator (on completion of each significant packaging stage) confirming the correct issued of bulk product and packaging materials.  Major equipment and packaging lines utilized with details of their preparation and cleaning this information can be recorded in an equipment log, including reference to the previous product processed.  Records of packaging operations carried out.  Recorded values of all in-process controls such as overprinting quality, dose control and detection system verification and initials of the persons completing them.  Samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting.  Quantities and company code reference of all printed packaging materials and bulk product issued, used, destroyed or returned to store; the yield of the packed product, so that reconciliation of the packaging operation can be completed with all calculations being recorded on the document – yields outside the acceptable yield should be investigated and the results reported.  Records of storage conditions prior to approval for sale.

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 Records of any problems; details of any deviations from the packaging instruction which should be authorized by production, quality department and other technical staff as detailed in the production deviation procedure.  Date of quality department approval for batch release. Note: Filling of sterile products requires documentation with similar information to the packaging records. Special documents are often designed due to more details being required concerning preparation and sterilization of all components, monitoring of the process and inspection of the final product. The extra elements should include:  Equipment, materials and packaging components used linked to records of how they were prepared, cleaned and sterilized facilitate tracing the records back to a particular sterilizing run.  Environmental check, filter integrity tests and checks on aseptic operation should be recorded; if these are recorded elsewhere they should be linked so that the quality department can review them prior to approval of the batch.  Date of quality department approval for next stage of production. l. i. Standard Operating Procedures Standard Operating Procedures (SOPs) are formal written documents, which detail how an operation is performed. They are required for all operations, which can affect the safety, identify, strength, quality and purity standards of medicinal products. ii. A SOP should inform the user of the following:  Why the procedure has been written.  Where the procedure is used.  When the procedure is to be used.  What actions are required?  How the action is performed.  Who is involved? iii. The following points should be considered when writing a SOP:  Use dedicated stationary and retain the same format.  Keep it simple; if events or actions occur in a certain order, retain that order in the SOP and avoid afterthoughts.  Keep references to other SOPs or sections with the SOP to an absolute minimum as they only make the document less user friendly.  Consider the use of tables, diagrams of flow charts, which can often explain a requirement more clearly.  Keep the text numbering system simple.
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 Consult (in the drafting stage) with the people who will use the SOP to confirm that it is understood and accurately reflects the task to be performed.  Avoid large cascades of sub-paragraphs-three should be a maximum. iv. The following headings should be considered:  TITLE  INTRODUCTION Use only when useful background information can be provided which will assist user understanding.  PURPOSE  Describe the object of the procedure (Why)  SCOPE What areas of activity are covered e.g. Company, Division, Department (Where)  POLICY State the Company or Department policy or refer to a separate policy document.  SAFETY Detail or make reference to safety procedures.  FREQUENCY Specify how often the procedure should be used e.g. after each batch, annually (When)  PROCEDURE Define the actions and who should complete them. Wherever possible the action should be written in the form of a positive instruction. Ideally the first word should be the command i.e. Draft, Clean, Submit, Calibrate, Complete etc. (What, How, Who)  DOCUMENT HISTORY This should details the history of the document with issue dates and reason for revision. Provision for a review date should be made.  CIRCULATION LIST  A list of all recipients of a copy. This should specify the job function name and copy number issued. v. vi. A SOP should be available which describes how all SOPs are written. Many procedures will be required to meet the requirements of the site quality assurance programme. However, a few examples are given in the following section with an indication of those elements, which should be considered for inclusion: Equipment Operation

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Each item of production and analytical equipment should have an operation SOP. As a minimum, the SOP should provide detailed operating instructions either directly or by reference to the suppliers operating manual. considered for inclusion, are:  Cleaning instructions.  Calibration and servicing requirements.  Function checks (functions which are critical to the equipment use that must be tested at a defined frequency) e.g. autoclave door seal integrity.  Use of equipment logbook, which is a record including all events associated with the equipment e.g. product processed and batch number, cleaning, breakdown and maintenance and calibration dates. Maintenance The maintenance procedure for each item of equipment, facility or service should be primarily based on the supplier’s recommendations and the monitoring of performance either by time or function. The following elements should be considered within the Maintenance Procedure:  Frequency.  Methods to be used.  Responsibility.  Recording of work and archiving records.  Reference to the procedure for seeking approval before taking the item offline to perform the maintenance and its subsequent return to operation, i.e. a work authorization.  Function testing, if not already included in the specific equipment SOP to demonstrate compliance with predefined operational parameters. Calibration (refer to Appendix 3 for an example of a document (. Instruments associated with equipment, facilities or services must have a defined calibration procedure. The following elements should be considered within the Calibration Procedure:  Frequency of calibration (to include re-verification following repair or modification).  What is to be checked and within what parameters.  Equipment and standards to be used; standards should be certified to a recognized national standard.  Methods of calibration.  Responsibility.
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Other elements, which could be

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 Recording, reporting and archiving results.  Actions to be taken if calibration fails.  Status labeling (each item should be clearly labeled with a calibration due date).  Instruction that no measuring system may be used unless it carries a current certificate of calibration. Sanitation The following elements should be considered within the cleaning procedure:  Frequency and times.  Date of cleaning.  How to handle spillages.  Persons responsible for cleaning.  Cleaning equipment, which is to be used, its storage and maintenance.  Cleaning agents (list of approved agents, preparation instruction, shelf life, rotation, etc.)  Completion of cleaning records.  Methods of verity cleaning and check on its effectiveness.  How and when to check manufacturing equipment for cleanliness.  Methods of identifying that equipment is clean or dirty labeled to show status.  Methods of cleaning to be used between the same product and different products. The procedures may be stand-alone or form part of an equipment, service of facility procedure. Note: Cleaning methods used in specialized manufacturing nits i.e. sterile areas will include disinfections. Disinfections are concerned with lowering the level of microbiological contamination and should be used in conjunction with traditional cleaning. Returns The following elements should be considered within the returns procedure:  Receipt procedure which would normally require the completion of a returned goods note; this would specify product name, quantity returned, expiry date and reason for return.  Responsibility for reception, booking in review of goods and sentencing (e.g. destroy, redress, recover, return to stock) with sentencing criteria; these criteria

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should include financial limits below which the product will be destroyed without further review, due to a short residual shelf life or analytical costs.  Particular consideration should be given to the criteria determining the acceptability of return of goods requiring controlled low temperature storage.  Responsibility for approving credit. Customer Complaints The following elements should be considered within a complaints procedure: Ensure that complaints, whatever their origin or method of reporting are channeled to the appropriate group within the company for acknowledgement and action. Responsibility for each of the following phases:  Recording  Investigation; this should include a requirement to review previous history and assess the risk to other batches which may be subject to the same problem.  Internal reporting.  Assessment of cause.  Corrective action.  Response to complainant.  Notification of serious complaints, which may require a product recall.  Methods of retrieval and trending data by complaint category.  Annual review of complaint performance. Product Recall The following elements should be considered within the Product Recall procedure:  Definition of situation, which may require a recall to be instigated.  Method of halting the distribution.  How the situation will be reported and to whom (e.g. the local health authority).  Means of notifying the customer and implementing a recall; this will depend on the risk to the patient.  Capability of being put into operating at any time, within or outside working hours; the SOP should include a list of emergency and out-of-hours contracts.  Content of the recall committee and chairman.  Investigation into the cause of the recall and reporting, identification of actions, timescale and responsibility for completing the actions.  Reconciliation procedures to account for the location of all recalled stock.  Requirement to perform dummy recalls to ensure the procedure can be carried out in a practicable and timely fashion.

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Environmental Monitoring The following elements should be included within one or more procedures:  Physical monitoring procedures.  Biological monitoring procedures.  Frequency of monitoring and monitoring period.  Interpretation and reporting (including trend analysis and out of limit reporting).  Specifications with warning and action limits. Health and Hygiene All site personnel should be made aware both of the risk that communicable diseases can have on the manufacturing environment that product may have on their health and the precautions to be taken to avoid exposure. The instruction should form part of a documented training program. Personnel should also be instructed on the important of personal hygiene. The following should be included in the appropriate procedure:  Company screening policy, which would include details of personnel requiring health checks, frequency and types of screening to be performed.  Reporting by personnel of diseases or open lesions to ensure they do not come into contact with the exposed product.  Screening of personnel by interview of return from a period of sickness.  Clothing, washing and changing procedures.  Visitor requirements (clothing, no-go areas etc.)  Cleaning and storage of clothing.  General hygiene requirements i.e. no smoking, drinking, chewing or eating in production and quality areas.  Requirements relating to wearing of jewelry. Self Inspection This should be a routine activity that involves a comprehensive check by a team of site personnel or independent experts on all of the site activities, which impact on quality. This activity forms an integral part of the periodic assessment of quality performance within the site and it should consider two main areas;  Housekeeping.  Compliance with the principles of GMP and in-house procedures. There should be a procedure, which describes the following elements:  Preparation of an annual inspection programme; this program should specify the area to be inspected, date of inspection and inspection team members.  Guidance on the scope of the inspection; a checklist may prove to be useful in this respect.
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 Reporting procedures which should include a requirement to detail each defect that has been observed with the remedial action required; a person responsible for the completion of the corrective action should be named together with the date by which the action must be completed.  A formalized method of follow up should be in place to ensure that each action has been satisfactorily completed; this should also be revivified at the next inspection. m. Training It is necessary for all personnel working in any area associated either directly (production) or indirectly (planning, purchasing) with the manufacture of pharmaceutical medicines receive training at the time of recruitment and reassessment at specified interval thereafter. i. Instructions There should be a SOP, which describes the following elements:  Company training policy.  Type of training programme available i.e. induction, GMP, technical skills.  Training schedule.  Training of persons responsible for training.  The frequency of training.  Training requirements when changes are made to existing procedures or equipment.  Assessment / performance measurement procedures.  Training records both formal and informal (on-the-job). Individual training modules can be developed from this procedure. ii. Records Training records must be kept for all personnel, detailing both on (e.g. machine operation) and off-the-job training (e.g. GMP training). These should also include a job description and curriculum vitae. The training record should state when the training was started, completed, who carried out the training and an acknowledgement by the trainee that he / she understood the training. A questionnaire is often useful in this respect. From these individual training records a matrix showing all the personnel in an area can be developed, identifying which persons have been trained to perform which tasks. Such records are particularly useful when allocating resources. A simple computer system may be developed to provide the same information. They should describe in detail the steps by which the employees has to become proficient in his job.

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n. Validation Procedures and Records Validation is a documented procedure for obtaining, recording and interpreting the results needed to show that a manufacturing system will consistently yield a product complying with predetermined specifications. Validation can be split into three main component parts:  Installation qualification (IQ)  Operational qualification (OQ)  Process Qualification (PQ) Other qualifications such as design, system, and performance are also used. One completion of all the individual parts, the whole process or product can be said to be validated. A validation plan should be written prior to commencement of any validation. It is important that each component has a qualification protocol, which details the work to be done, the acceptance criteria and a qualification record giving the results. Results outside predefined limits should be assessed and a record made whether they are acceptable or not. If they are acceptable an addendum to the protocol defining the justification for the revised limits should be issued. The content of these protocols will be based on an approve design specification. IQ can include trails prior to installation, quality plans during building / construction (this is sometimes extracted and called construction qualification) and data concerning installation. OQ includes checks of correct operation of the equipment or facility over the full range of its design specification. PQ is the qualification of the process; this may include checking the process between the highest and lowest control parameters, cleaning qualification and acceptability of reworking procedures. Note: PQ is sometimes used to denote Performance Qualification of plant or computer system. This monograph includes this activity under OQ. The following qualifications often have their own specific documentation:  Computer system qualification.  Instrument calibration. i. Validation Plan The plan should include the following elements:  Objective of validation exercise.  What is being validated (description with reference to specifications).  Degree and scope of validation with justifications.
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 List of protocols (to demonstrate conversion to ‘Scope and Objectives’).  Person leading the validation exercise, the team undertaking the validation and personnel resource required to complete the work.  Material resource required.  When the validation will be done.  Reference to relevant procedures (SOPs).  Documentation and authorization requirements.  Periodic validation, checking or confirmation.  Signed authorization by quality department, technical expert and the owner. This particularly for a large project may be termed a Validation Master Plan. ii. IQ Protocol The protocol should be written and authorized before installation commences and should include the following elements:  Item being installed.  Checks to be completed during construction and installation, including acceptance criteria with definition of, or reference, to any methods to be used.  Description of plant with reference to which installation drawings should be produced.  Service requirement.  Acceptance checks against the purchase specification.  Change parts and spare parts required.  Control system to be installed with plant.  Instrumentation and calibration requirements.  Specific design specifications that are to be complied with.  Operating and cleaning procedures to be identified (they may be written in draft at this stage).  Maintenance programme to be prepared.  Signed authorization by the quality department, technical expert and the owner. iii. IQ Record The record should include the following elements:  Name of plant, reference number, date of installation and reference to original plant specification.  Records with signatures of critical checks completed during construction / installation.  List of as-installed drawings.  Details of services connected during plant installation.
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 List of spare parts and change parts available.  List of control systems.  Instrument list.  Reference to operating procedure, maintenance procedures and schedules, cleaning procedures and training materials.  Records of any engineering commissioning trial or test prior to OQ a record of all modifications completed during or after such trials should be made.  Signed authorization by the quality department, technical expert and the owner. iv. OQ Protocol The protocol should be written and authorized before operational tests commence and should include the following elements:  Item being qualified.  Operating and cleaning procedures to be written.  Basic equipment function to be checked against an approved specification including acceptance criteria / limits.  Process simulations to be checked including acceptance criteria / limits.  Reference to test equipment and test procedures.  Signed authorization by the quality department, technical expert and the owner. v. OQ Record The record should include the following elements:  Name of plant, reference number and reference to original plant specification.  Test equipment certification.  Record of basic function checks with results; signature of person performing work with the date when work was completed.  Statement as to whether or not results comply with the acceptance criteria / limits; results that are outside the limits should be reviewed and the alternatives considered.  Void: an explanation for omitting any results should be given.  Unacceptable on review: an addendum to the protocol should be authorized giving the reason for a change to the acceptance criteria / limits with full justification.  Singed authorization by the quality department, technical expert and the owner. vi. Process Qualification Protocol The protocol should be written and authorized before the process work commences and should include the following elements:  Process to be qualified.
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 Product and number of batches to be validated.  Description of each process item to be qualified including acceptance criteria / limits.  Reference to test equipment and procedures.  Analytical specification.  Signed authorization by the quality department, technical expert and the owner. vii. Process Qualification Record  Definition of process qualified.  Name of product validated.  Record of process checks competed with results, signature of persons performing work with date work was completed.  Statement as to whether or not results company with the acceptance criteria / limits; results that are outside the limits should be reviewed and the alternative should be considered.  Signed authorization by the quality department, technical expert and the owner. Vii. Process Qualification Record The record should include the following elements:  Definition of process qualified.  Name of product validated.  Record of process checks completed with results, signature of person performing work with date work was completed.  Statement as to whether or not results comply with the acceptance criteria / limits; results that are outside the limits should be reviewed and the alternatives given in 5.10.5 considered.  Signed authorization by the quality department, technical expert and the owner. viii. Validation Report (Final Report, Summary Report etc). This report summarizes the work completed in the various qualification reports and confirms that the process / product is now validated. ix. Distribution Records In order to facilitate recall records of distribution should be kept which include for each batch of product, the name, addresses, telephone, telex and facsimile number of all persons, companies and other organizations to whom that batch of product has been supplied. These records should include distribution to export markets and medical samples. Where temperature or humidity sensitive products are involved, records of transit should also be kept.

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x. Technical Agreements (Contract Manufacture / Analysis) A Technical Agreement should be drawn up between contract given and contract acceptor defining their respective responsibilities. An agreement is normally part of a contract between the companies involved. It should be drawn up and agreed by suitably competent and knowledgeable person from both companies. The agreement should reflect the requirements of the marketing authorization for the products, which is described. It should define the mechanism by which a Qualified Person reviews the manufacture and control of batches of products prior to release for sale. Responsibilities should be defined for purchasing, sampling, testing and releasing starting materials, (consideration should be given to those items supplied by the contract giver), for carrying out manufacturing controls (in-process control) and for quality control of the finished product, (sampling, testing and releasing). Retention of manufacturing, testing and distribution records, reference samples (starting materials, bulk product and packed product) should be defined in the agreement. The contract giver (the product marketing authorization holder) retains responsibility for these actions. Computer and Electronic Documentation Documentation is held on paper or on an electronic database for either archiving or for the purpose of recording process data. The principles and controls applied to security and GMP should be similar and equally effective. The following elements should be considered specifically for such systems:  A system description (often a flow chart is useful in this respect), which covers the main features of the system and how they interact with other system and procedures.  Access to the system and within the system must be restricted to nominated personnel, each with individual passwords, which are subject to frequent change and additional check such as an identity badge, should be considered.  Changes to original data must be flagged and traceable through an internal audit trial must include the reason and authorization for the change.  A requirement for regular backup of data.  Accessibility of data is durability to storage and how long the data should be archived.  The procedure to be followed in the event of system failure i.e. backup procedures; these should be regularly challenged.  Impact of upgrade to hardware and software since original archiving must be assessed to ensure accurate retrieval.
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ABC PHARMACEUTICALS Product: Solution for injection 2 mg / ml Document No. 100/04D dtd. Aug. 1994 BATCH MANUFACTURING RECORD Code: 023456 Batch size: 100 MATERIAL ISSUE Material Code E342H Active Sulphate Ph. Eur. WIOOD Water for injection bulk to 100L NA to 100 L Material Quality Required 200g A. No. Factor Quantity Issued Weighted By Checked By Batch No. AB123 Page 1 of 9

Supervisor Check: Written By: Mfg. Asso.:

Date: Quality Authorization: Dept. Issued by:

Date:

Date:

Date:

Date:

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ABC PHARMACEUTICALS Product: Solution for injection 2 mg / ml Document No. 100/04D dtd. Aug. 1994 A. 1. SAFETY PRECAUTION: Refer to Hazard Profile Sheets for additional protective equipment necessary when handling materials in the product, especially when handling the following Active Sulphate: Wear dust mask as specified in SP1(b) when carrying out dust creating operations. Wear gloves as specified in SP1(a) when handling product. All equipment in these records is specified by a standard operating procedure. SPD 126, SPD 218 and SPD316. If this batch is the first of a run of batches the Department Supervisor must sign here to verify that the equipment and area to be used is clean and in a satisfactory condition. Supervisor: Date: BATCH MANUFACTURING RECORD Code: 023456 Batch size: 100 Batch No. AB123 Page 2 of 9

Written By:

Mfg. Asso.:

Quality Authorization:

Dept. Issued by:

Date:

Date:

Date:

Date:

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ABC PHARMACEUTICALS Product: Solution for injection 2 mg / ml Document No. 100/04D dtd. Aug. 1994 Storage: Store at between 15-28C. The product should be filled within 24 hours of completion of solution manufacture. RECONCILIATION Weight Manufacture (A) Weight taken as sample (B) Weight recorded as rejected (C) Yield for packaging (D) Unaccounted loss E = A-B-C-D Unaccounted loss E = A-B-C-D % loss =
E x 100 A

BATCH MANUFACTURING RECORD Code: 023456 Batch size: 100 Batch No. AB123 Page 9 of 9

g g g g g g g

This batch was not completed in accordance with the manufacturing instructions. Operator: Supervisor: Approved for packaging: Quality Assurance: Written By: Mfg. Asso.: Date: Date: Date: Date: Quality Authorization: Dept. Issued by:

Date:

Date:

Date:

Date:

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ABC PHARMACEUTICALS Product: Tablets 100 x 100 mg Bottles Document No. 1234-01 Dtd. April, 92 PACKAGING RECORD SHEET Code: 023456 Batch size: 100 MATERIAL LIST Material Code 0001 0002 0003 0004 0005 0006 Label Carton Leaflet Bottle Caps Tablets PROCESS CONTROLS 1. Setup Bar Code label and carton. 2. Function check all detection equipment on start up and after breakdown 3. Check the first complete pack off line for correct assembly, coding and overprinting. 4. Check the contents of 1 bottle on start up after a breakdown and every 30 minutes thereafter. 5. Record all check on the Packaging Record Sheet. PACKAGING INSTRUCTIONS 1. Fill each bottle with 100 tablets and cap. 2. Label each bottle and place in carton. 3. Insert one folded leaflet into each other and close. 4. REFER TO SAFETY HAZARD SHEET NO. 1. 5. STORAGE: No specific instruction. OVERPRINTING INSTRUCTIONS 1. Carton DOM EXP Batch No. Written By: Mfg. Asso.: 2. Label DOM EXP Batch No. Quality Authorization: A. Author Date: Dept. Issued by: Material Quantity Issued Batch No. Issued by Received By Batch No. Page 1 of 2

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ABC PHARMACEUTICALS Product: Tablets 100 x 100 mg Bottles Document No. 1234-01 Dtd. April, 94 PACKAGING RECORD SHEET Code: 023456 Batch size: 100 Batch No. Page 2 of 2

AREA / LINE CLEARANCE Line No.: Clearance 1 Check: Start data / time: Labelle Received Used Spoils Samples Surplus Total Accounted % Accounted Status Surplus Check Signatures FINAL PACK YIELD Samples: Packs Warehouse COMMENTS
st

Previous Product: Batch No. Clearance 2nd Check: Finish date / time Carton Leaflet Tables

COMPLETED RECORD CHECK Production: Date: Quality Department: Date:

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ABC PHARMACEUTICALS Product: Code: TIME Label Carton Leaflet DETECTION EQUIPMENT FUNCTION CHECK TIME Label Bar Code Carton Bar Code Overprint Label CONTENTS CHECK TIME Label Code Dom Exp Batch Code Dom Exp Batch CONTENTS CHECK TIME No. in bottle Checked by CONTENTS CHECK TIME No. in bottle Checked by CONTENTS CHECK TIME No. in bottle Checked by
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PACKAGING CONTROL RECORD Batch No. Date: FINISHED PACK CHECK

Documentation Procedures
ABC PHARMACEUTICALS – QUALITY DEPARTMENT MATERIAL SPECIFICATION Material: Sulphate Eur. Sample req. Test: Container type and size: Test Appearance Solubility Specification Fine, white crystalline powder Soluble in one part of water in chloroform, ethanol. Loss on drying Ash Chloride Related substances Not more than 1.05% Not more than 0.15% Not more than 100 ppm No one impurity more than 0.20% and impurities more than 0.50%. Abnormal toxics Assay Complies with Ph. Eur requirements. Content of sulphate (on dry basis 99.0 to 101.0%) Prepared By: Checked By: Approved By: Material Code: Specification No. Reference: Approved Suppliers:

Date:

Date:

Date:

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ABC PHARMACEUTICALS – QUALITY DEPARTMENT CERTIFICATE OF ANALYSIS Solution for Injection 2 mg / ml Specification No. Batch No.: Expiry Date: TEST RESULTS Test Appearance Assay pH Related substances Specification Gear, Colourless solution 2.95 to 2.05 mg / ml 5 to 7.5 Results Complies 2.01 mg 6.9

%0 one impurity more than Two impurities 0.06 to 0.13% 0.30% Total impurities not more 0.21% than 0.75

Abnormal toxicity Sterility

Complies Ph. Eur. Complies Ph. Eur.

Complies Complies

This is to certify that the approve batch has been manufactured and tested to compile with the principles of GMP and in accordance with the product license.

Signed:

Date:

Quality Department Manager B.Sc (Chem.)

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