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Documentation and Records: Harmonized GMP RequirementsKT Patel and NP ChotaiAbstract‘If it’s not written down, then it didn’t happen!’ The basic rules in any good manufacturing practice (GMP) regulationsspecify that the pharmaceutical manufacturer must maintain proper documentation and records. Documentation helps tobuild up a detailed picture of what a manufacturing function has done in the past and what it is doing now and, thus, itprovides a basis for planning what it is going to do in the future. Regulatory inspectors, during their inspections ofmanufacturing sites, often spend much time examining a company’s documents and records. Effective documentationenhances the visibility of the quality assurance system. In light of above facts, we have made an attempt to harmonizedifferent GMP requirements and prepare comprehensive GMP requirements related to ‘documentation and records,’followed by a meticulous review of the most influential and frequently referred regulations.Keywords: Documentation and records, good manufacturing practices, quality assuranceINTRODUCTIONTragic incidentIt is a truism that it takes a disaster to happen for people, and especially regulators, to wake up and review the acceptedway of doing things. So, too, with the issue of drug safety and drug quality.[1]The 1972 Devonport, UK, incident resulted in at least five deaths when drug products designed to be sterile becamecontaminated and recipients developed infections. An unwritten change to autoclave operation, communicated orallybetween operators, resulted in dextrose intravenous solutions that were not uniformly sterile. The Clothier inquiry, whichexamined the causes and contributing factors, identified several violations of what we now consider basic goodmanufacturing practice (GMP).The chain of events that compromised the safety of the drug product included inadequate maintenance, inadequateunderstanding of autoclave operation, and regular deviations from the written production instructions (often as anattempt to compensate for equipment malfunction). Together, these factors resulted in a sterilization cycle that did notassure that all vials in the autoclave were sterilized; thus, some doses were safe, while others led to sepsis in patients whoreceived them. This incident helped to define sterility assurance in an operational way. Processes and requirements forequipment validation were created, and legal right of inspection was explicitly given to the agency.Validation was developed as a means of documenting systematic evaluation of the sterilization cycle — building in a safetyfactor — and identifying the critical parameters that need to be controlled to assure process performance. The concept thatquality must be designed into the process and cannot be achieved only by testing remains a central tenet of current goodmanufacturing practice (cGMP). In other words, how you make something helps to define its level of quality. Preventingerrors is more effective than finding rejects because it is not possible to detect all rejects.[2] The current requirement for’documented evidence’ may be driven by this event of Devenport.GOOD MANUFACTURING PRACTICESGMP is that part of quality assurance which ensures that products are consistently produced and controlled to the qualitystandards appropriate to their intended use. GMP is aimed primarily at diminishing the risk inherent in anypharmaceutical production. Such risks are essentially of two types: cross-contamination (in particular, with unexpected1 of 168/18/13 10:24 AM

contaminants) and mix-ups (for example, false labeling).[3]Worldwide, there are different official regulatory statements and guidelines, both national and international, for GMP forpharmaceutical (or ‘drug’ or ‘medicinal’) products. They may be regulations (as in the US, Japan, or Korea), directives (asin the EU), guides (as in the UK), codes (as in Australia), or a WHO code (as in many Southeast Asia Countries). Amongthem, the following stand out as the most influential and most frequently referenced:The US Current Good Manufacturing Practices for Finished Pharmaceuticals regulations (the US cGMPs).[4]The Guide to Good Manufacturing Practice for Medicinal Products of the European Union (the EC GMPGuide).[5]The ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients.[6]The World Health Organization (WHO) good manufacturing practices.[7]The other guidelines and regulations referred by the pharmaceutical manufacturers are as under:Schedule M ‘Good Manufacturing Practices and Requirements of Premises, Plant and Equipment forPharmaceutical Products,’ The Drugs and Cosmetics Act and Rules, India.[8]PIC/S Guide to Good Manufacturing Practice for Medicinal Products.[9]Center for Drug Evaluation and Research (CDER): Manufacturing, Processing, or Holding Active tation is the key to GMP compliance and ensures traceability of all development, manufacturing, and testingactivities. Documentation provides the route for auditors to assess the overall quality of operations within a company andthe final product.The 10 golden rules of GMP[11]Table 1 describes the 10 golden rules of GMP. Rule No. 3 and 5 describe the importance of documentation and records.Table 1The 10 golden rules of GMPBasics[12]The management of each operational site is required to define responsibility for origination, distribution,maintenance, change control, and archiving of all GMP documentation and records within that department orunit.Document owners are required to ensure that all aspects of documentation and records management specified inform of standard operating procedures (SOPs).All associates have the responsibility of ensuring that all GMP activities are performed according to the officialSOPs; any deviations in procedure are reported to their supervisor and are adequately documented.The local quality assurance unit has the responsibility of ensuring via organizational measures and auditing thatGMP documentation and records systems used within the operational unit are complete and comply with therelevant GMP requirements, and also that the requirements of the SOPs are followed.2 of 168/18/13 10:24 AM

Requirements for specific documents or record, including ownership, content, authorization, and change controlprocedures, has to be described or cross-referenced in the quality modules which relate to the subject of thedocument.General requirements[13]Good documentation constitutes an essential part of the quality assurance system. Clearly written proceduresprevent errors resulting from spoken communication, and clear documentation permits tracing of activitiesperformed.Documents must be designed, prepared, reviewed, and distributed with care.Documents must be approved, signed, and dated by the appropriate competent and authorized persons.Documents must have unambiguous contents. The title, nature, and purpose should be clearly stated. They mustbe laid out in an orderly fashion and be easy to check. Reproduced documents must be clear and legible.Documents must be regularly reviewed and kept up-to-date. When a document has been revised, systems must beoperated to prevent inadvertent use of superseded documents (e.g., only current documentation should beavailable for use).Documents must not be handwritten; however, where documents require the entry of data, these entries may bemade in clear legible handwriting using a suitable indelible medium (i.e., not a pencil). Sufficient space must beprovided for such entries.Any correction made to a document or record must be signed or initialed and dated; the correction must permitthe reading of the original information. Where appropriate, the reason for the correction must be recorded.Record must be kept at the time each action is taken and in such a way that all activities concerning the conduct ofpreclinical studies, clinical trials, and the manufacture and control of products are traceable.Storage of critical records must at secure place, with access limited to authorized persons. The storage locationmust ensure adequate protection from loss, destruction, or falsification, and from damage due to fire, water, etc.Records which are critical to regulatory compliance or to support essential business activities must be duplicatedon paper, microfilm, or electronically, and stored in a separate, secure location in a separate building from theoriginals.Date may be recorded by electromagnetic or photographic means, but detailed procedures relating to whateversystem is adopted must be available. Accuracy of the record should be checked as per the defined procedure. Ifdocumentation is handled by electronic data processing methods, only authorized persons should be able to enteror modify data in the computer, access must be restricted by passwords or other means, and entry of critical datamust be independently checked.It is particularly important that during the period of retention, the data can be rendered legible within anappropriate period of time.If data is modified, it must be traceable.There are various types of procedures that a GMP facility can follow. Given below is a list of the most common types ofdocuments, along with a brief description of each.1. Quality manual: A global company document that describes, in paragraph form, the regulations and/or parts ofthe regulations that the company is required to follow.2. Policies: Documents that describe in general terms, and not with step-by-step instructions, how specific GMPaspects (such as security, documentation, health, and responsibilities) will be implemented.3. Standard operating procedures (SOPs): Step-by-step instructions for performing operational tasks or activities.4. Batch records: These documents are typically used and completed by the manufacturing department. Batchrecords provide step-by-step instructions for production-related tasks and activities, besides including areas onthe batch record itself for documenting such tasks.3 of 168/18/13 10:24 AM

5. Test methods: These documents are typically used and completed by the quality control (QC) department. Testmethods provide step-by-step instructions for testing supplies, materials, products, and other production-relatedtasks and activities, e.g., environmental monitoring of the GMP facility.Test methods typically contain forms that have to be filled in at the end of the procedure; this is for documentingthe testing and the results of the testing.6. Specifications: Documents that list the requirements that a supply, material, or product must meet before beingreleased for use or sale. The QC department will compare their test results to specifications to determine if theypass the test.7. Logbooks: Bound collection of forms used to document activities. Typically, logbooks are used for documentingthe operation, maintenance, and calibration of a piece of equipment. Logbooks are also used to record criticalactivities, e.g., monitoring of clean rooms, solution preparation, recording of deviation, change controls and itscorrective action assignment.Hierarchical document system[12]The organization should establish a hierarchical document system as mentioned in Figure 1:Figure 1Hierarchical document systemThe regulations that a company is responsible for following (e.g., USFDA/EU GMP/ICH/Schedule M, etc.) shouldbe at the top of the document pyramid and should govern the directives of the sublevels.The level immediately beneath the regulations, level 1 documents (e.g., the Quality Manual), should break theregulations into parts specific to those that the company is required to follow. These documents should establishoverall principles and guidelines for how the company plans on developing, documenting, and implementing acCMP-compliant quality system. Top-level documents apply to all departments within a cGMP-compliantcompany and are not specific in nature.The next level, level 2, of documents in the hierarchical document pyramid should further break down the parts ofthe regulations into specific subjects or topics. These documents (e.g., Company Polices) should establishguidelines with which all subordinate level procedures must comply to ensure consistency across departments.Level 2 documents should not provide specific directive instructions or forms for documenting data but ratherprovide the overall intentions and guidelines governing critical programs or systems as well as explanation for therationale and program designs. These documents will apply to all departments within a GMP-compliantcompany.SOPs should be the next level in the document hierarchy after company policy documents. These types ofdocuments should provide specific step-by-step instructions for performing the operational tasks or activities thatwere talked about in the previous levels (for example: SOP titled ’Writing, Revising, Numbering, and DistributingControlled Documents’). Level 3 documents (i.e., SOPs) should be department specific or function specific.The last level of documents in a document hierarchical structure are level 4 documents. These documents are themost specific in nature, (e.g., batch record, test methods, validation procedures). They apply to a specificdepartment, product, equipment, or process. Level 4 documents provide step-by-step instructions for productionrelated tasks and activities as well as provide a means for documenting such tasks using, for example, data sheets,forms, or batch records. The details outlined in these documents may override directions given in other leveldocuments. (For example: the company’s documentation SOP may state that numbers be rounded off to three4 of 168/18/13 10:24 AM

significant figures; the batch record, on the other hand, may state that all numbers be expressed in scientificnotation. Thus, instructions in level 4 documents, which are specific to a particular process, can overrule theinstruction mentioned in level 3 documents, which are general in nature. The document hierarchy pyramid is oneway of organizing a company’s documents.More/less levels may be added/subtracted to meet the company’s specific needs.HARMONIZED REQUIREMENTThe harmonized requirements were prepared after taking into consideration the above mentioned guidancedocuments/regulatory requirements.[4–10]Site master fileThe manufacturer should prepare a succinct document in the form of a ‘Site Master File,’ containing specific and factualGMP about the production and/or control of pharmaceutical manufacturing procedures carried out at the premises. Itshould contain the descriptions of the following:General information:Brief information on the firmPharmaceutical manufacturing activities, as permitted by the licensing authorityOther manufacturing activities, if any, carried out on the premisesType of products licensed for manufacture, with flowcharts detailing procedure and process flowNumber of employees engaged in the production, quality control, storage and distributionUse of outside scientific, analytical, or other technical assistance in relation to manufacture and analysisShort description of the quality management system of the firmProducts details registered with foreign countriesPersonnel:Organizational chart showing the arrangements for quality assurance, including production and quality controlQualification, experience, and responsibilities of key personnelPremises:Simple plan or description of manufacturing areas drawn to scaleNature of construction and fixtures/fittingsBrief description of ventilation systems. More details should be given for critical areas with potential risk ofairborne contamination (schematic drawing of systems). Classification of the rooms used for the manufacture ofsterile products should be mentioned.Special areas for the handling of highly toxic, hazardous, and sensitizing materials.Brief description of the water system (schematic drawings of systems), including sanitation.Description of planned preventive maintenance programs for premises and of the recording system.Equipment:Brief description of major equipment used in production and in the quality control laboratories (a list ofequipment required)Description of planned preventive maintenance programs for equipment and of the recording systemQualification and calibration, including the recording systems, and arrangements for computerized systemsvalidation5 of 168/18/13 10:24 AM

Sanitation:Written specifications and procedures for cleaning manufacturing areas and equipmentDocumentation:Arrangements for the preparation, revision, and distribution of documentsNecessary documentation for the manufactureAny other documentation related to product quality that is not mentioned elsewhere (e.g., regardingmicrobiological control of air and water)Production:Brief description of production operations using, wherever possible, flow sheets and charts specifying importantparametersArrangements for the handling of starting materials, packaging materials, and bulk and finished products; thisincludes the arrangements for sampling, quarantine, release, and storage.Arrangements for the handling of rejected materials and products.Brief description of the general policy for process validation.Quality control:Description of the quality control system and of the activities of the quality control department. Procedures forthe release of the finished products.Loan license manufacture and licensee:Description of the way in which compliance with GMP by the loan licensee should be assessed.Distribution, complaints, and product recall:Arrangements and recording system for distributionArrangements for the handling of complaints and product recallsSelf inspection:Short description of the self-inspection system, indicating whether an independent and experienced externalexpert is to be involved in evaluating the manufacturer’s compliance with GMP in all aspects of productionExport of drugsProducts exported to different countriesComplaints and product recall, if anyDocumentation system and specificationsDocumentation is an essential part of the quality assurance system and, as such, should be related to all aspects of GMP.Its aim is to define the specifications for all materials and the method of manufacture and control, to ensure that allpersonnel concerned with manufacture have the information necessary to decide whether or not to release a batch of adrug for sale, and to provide an audit trail that will permit investigation of the history of any suspected defective batch.The specifications should describe in detail the requirements with which the products or materials used or obtainedduring manufacture have to conform. They serve as a basis for quality evaluation.Manufacturing formulae and processing and packaging instructions should specify all the starting materials used anddescribe all processing and packaging operations. Procedures should give directions for performing certain operations,6 of 168/18/13 10:24 AM

e.g., cleaning, clothing, environmental control, sampling, testing, and equipment operation. Records should provide ahistory of each batch of product, including its distribution, and also of all other relevant circumstances pertinent to thequality of the final product.Written records should be maintained so that data can be used for evaluating, at least annually, the quality standards ofeach drug product to determine the need for changes in drug product specifications or manufacturing or controlprocedures. Written procedures should be established and followed for such evaluations and must include provisions for:A review of a representative number of batches, whether approved or rejected and, where applicable, the recordsassociated with the batch.A review of complaints, recalls, and returned or salvaged drug products, and of the investigations conducted.All documents related to the manufacture of intermediates, active pharmaceutical ingredients (API), and finishedproducts should be prepared, reviewed, approved, and distributed according to written procedures. Such documents canbe paper-based or in electronic form. Documents should be approved, signed, and dated by the appropriate responsiblepersons. No document should be changed without authorization and approval.Each specification for raw materials, intermediates, final products, and packing materials should be approved andmaintained by the quality control department. Periodic revisions of the specifications must be carried out wheneverchanges are necessary.The issuance, revision, superseding, and withdrawal of all documents should be controlled, with maintenance of revisionhistories. When a document has been revised, systems should be operated to prevent inadvertent use of supersededdocuments. Superseded documents should be retained for a specific period of time.Periodic revisions of the specifications may be necessary to comply with new editions of the national pharmacopoeia orother official compendia.Documents should have unambiguous contents: the title, nature, and purpose should be clearly stated. They should be laidout in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The process ofreproduction of working documents from master documents must not allow any error to be introduced through thereproduction process.A procedure should be established for retaining all appropriate documents (e.g., development history reports, scale-upreports, technical transfer reports, process validation reports, training records, production records, control records, anddistribution records). The retention periods for these documents should be specified.All production, control, and distribution records should be retained for at least 1 year after the expiry date of the batch.For APIs with retest dates, records should be retained for at least 3 years after the batch is completely distributed.Documents should not be handwritten; however, where documents require the entry of data, these entries may be made inclear, legible, indelible handwriting. Sufficient space should be provided for such entries. Any alteration made to the entryon a document should be signed and dated; the alteration should permit the reading of the original information. Whereappropriate, the reason for the alteration should be recorded.During the retention period, originals or copies of records should be readily available at the establishment where theactivities described in such records occurred. Records that can be promptly retrieved from another location by electronicor other means are acceptable.Data may be recorded by electronic data processing systems or photographic or other reliable means, but detailedprocedures relating to the system in use should be available and the accuracy of the records should be checked. Ifdocumentation is handled by electronic data processing methods, only authorized persons should be able to enter ormodify data in the computer, and there should be a record of changes and deletions. Access should be restricted by7 of 168/18/13 10:24 AM

passwords or other means and the result of entry of critical data should be independently checked. Batch records that areelectronically stored should be protected by back-up transfer onto magnetic tape, microfilm, paper, or other means.Specifications should be established and documented for raw materials, intermediates (where necessary), andAPI/formulations, as well as for labeling and packaging materials. In addition, specifications may be appropriate forcertain other materials, such as process aids, gaskets, or other materials used during the production of intermediates orAPI/formulations that could critically impact on quality. Acceptance criteria should be established and documented forin-process controls.If electronic signatures are used on documents, they should be authenticated and secure.Equipment cleaning and use recordRecords of major equipment use, cleaning, sanitization and/or sterilization, and maintenance should show the date, time(if appropriate), product, and batch number of each batch processed in the equipment and the name and signature of theperson who has performed the cleaning and maintenance. The persons performing and double-checking the cleaning andmaintenance should date and sign or initial the log, indicating that the work was performed. Entries in the log should be inchronological order.Cross-contamination should be avoided by appropriate technical or organizational measures, for example:Production in segregated areas (required for products such as the penicillins, live vaccines, live bacterialpreparations, and some other biologicals), or by campaign (separation in time) followed by appropriate cleaningProviding appropriate air-locks and air extractionMinimizing the risk of contamination caused by recirculation or re-entry of untreated or insufficiently treated airKeeping protective clothing inside areas where products with special risk of cross-contamination are processedUsing cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of equipment is acommon source of cross-contaminationUsing ‘closed systems’ of productionTesting for residues and use of cleaning status labels on equipmentIf equipment is dedicated to manufacturing one intermediate or API, then individual equipment records of differentactivities like cleaning, maintenance, batch log, etc., are not necessary, provided the batch record has complete traceabilityof this information. In case of formulation manufacturing, the appropriate cleaning procedure should be established toensure removal of any residue of the previous product.Records of raw materials, intermediates, labeling, and packaging materialsRecords should be maintained, including:The name of the manufacturer; identity and quantity of each shipment of each batch of raw materials,intermediates, or labeling and packaging materials; the name of the supplier; the supplier’s control number(s) (ifknown) or other identification number; the number allocated on receipt; and the date of receipt;The results of any test or examination performed and the conclusions derived from this;Records tracing the use of materials;Documentation of the examination and review of labeling and packaging materials for conformity withestablished specifications;The final decision regarding rejected raw materials, intermediates, or labeling and packaging materials.Starting materials in the storage area should be appropriately labeled. Labels should bear at least the followinginformation:8 of 168/18/13 10:24 AM

The designated name of the product and the internal code reference, where applicableThe batch number given by the supplier and, on receipt, the control or batch number (if any) given by themanufacturer; these must be documented so as to ensure traceabilityThe status of the contents (e.g., on quarantine, on test, released, rejected, returned, recalled, etc.)Where appropriate, an expiry date or a date beyond which retesting is necessaryMaster (approved) labels should be maintained for comparison with issued labels.Master production instructions/master production and control records (MPCR)/master formula card (MFC)To ensure uniformity from batch to batch, master production instructions for each intermediate or API/finished productshould be prepared, dated, and signed by one person and independently checked, dated, and signed by a second person inthe quality unit(s).Competent persons experienced in production and quality control should be responsible for the content and distributionwithin the firm of instructions and master formulae. These should be duly signed and dated.Outdated master formulae should be withdrawn but retained for reference. Copies of the master formula should beprepared in a manner that will eliminate any possibility of transcription error.In certain circumstances, for example, in the first production runs following pilot development, the master formula mightneed to be amended. Any amendments must be formally authorized and signed by competent person(s). The amendeddocument should be replaced at the earliest opportunity by a newly prepared master formula.Processing should be carried out in accordance with the master formula. Master production instructions should include:The name of the intermediate/API/formulation being manufactured and an identifying document reference code,if applicableA complete list of raw materials and intermediates (designated by names or codes sufficiently specific to identifyany special quality characteristics)An accurate statement of the quantity or ratio of each raw material or intermediate to be used, including the unitof measure. Where the quantity is not fixed, the calculation for each batch size or rate of production should beincluded. Variations to quantities should be included wherever justifiedThe production location and major production equipment to be usedDetailed production instructions, including the: Sequences to be followed Ranges of process parameters to be used The methods, or reference to the methods, to be used for preparing the critical equipment (e.g., cleaning,assembling) Sampling instructions and in-process controls, with their acceptance criteria, where appropriate Time limits for completion of individual processing steps and/or the total process, where appropriate Expected yield ranges at appropriate phases of processing or time.Where appropriate, special notations and precautions to be followed, or cross-references to theseInstructions for storage of the intermediate or API/semi-finished formulations to assure its suitability for use;instructions should cover the labeling (specimen labels and packaging materials and special storage conditionswith time limits, where appropriate).Batch production records/batch production and control records (BPCR)/batch manufacturing record (BMR)Batch production records should be prepared for each intermediate and AP

DOCUMENTATION Documentation is the key to GMP compliance and ensures traceability of all development, manufacturing, and testing activities. Documentation provides the route for auditors to assess the overall quality of operations within a company and the final product. The 10 golden rules