9.22 Do procedures exist for
• self inspection?
• release or rejection of products or raw material?
• product complaints?
• product recalls?
• local stability testing?
• storage of reference samples?
• validation of analytical procedures?
9.23 Specifications available for 6.7 • raw materials?
• bulk products?
• packaging materials?
9.24 Analytical procedures for every product? 9.25 Are Basel methods followed? 9.26 Validation of locally developed test methods?
9.27 Sampling procedures available for 6.7 • raw materials?
• bulk products?
• packaging materials?
9.28 Suppliers certificates available? 6.7 9.29 Calibration program for analytical instruments installed? 6.7 9.30 Maintenance program for analytical instruments? 6.7 9.31 Retention system for QC records? 6.8 9.32 Batch documents stored for expiry+ 1 year or 5 years (EEC
75/319, article 22) minimum?
6.8
9.33 Are original data like notebooks stored in addition to the batch documents?
6.10
9.34 Can the original data be traced back easily and quickly from the analytical report number or batch number?
6.10
9.35 Are trend analyses being performed for 6.9 • analytical results?
• yields?
• environmental monitoring data?
Sampling
9.36 Written procedures for taking samples? 6.11 9.37 Do procedures define
• method of sampling?
• necessary equipment?
• quantity of the sample?
• subdivision of the sample?
• sample container?
• labeling of samples?
• storage conditions?
• cleaning and storage of sampling equipment?
• identification of containers sampled
9.38 Are samples representative for the batch they are taken from (sampling plan)?
6.12
9.39 Are critical steps being surveilled and validated by additional sampling (e.g., beginning or end of a process).
Compliance 1 2 3 Remarks EU-Guide
9.40 Sample containers labeled with 6.13 • name of the content
• batch number
• date of sampling
• batch containers sampled
9.41 Are samples taken by QC/QA?
9.42 Reference samples retained for validity +1 year? 6.14 9.43 Storage of reference samples under the recommended storage
conditions?
6.14
9.44 Finished products stored in the final packaging? 6.14 9.45 Quantity of the reference sample makes 1 (better 2) complete
reanalysis possible?
6.14
9.46 Sample room secure? 9.47 Sample room neatly organized and not overcrowded?
Testing
9.48 Are the applied analytical methods validated? 6.15 9.49 Analytical methods in compliance with the registration? 6.16 9.50 Are all results recorded and checked for correctness? 6.16 9.51 Are all calculations checked? 6.16 9.52 Do the testing protocols contain 6.17
• name and galenical form of material?
• batch number?
• supplier if applicable?
• specification reference?
• method reference?
• analytical results?
• reference to analytical certificates?
• date of the analysis?
• name of the analyst?
• name of the person verifying the data?
• statement of release or rejection?
• date and sign of the release person?
9.53 Are all IPC methods in production approved by QC? 6.18 9.54 Are written methods available for the preparation of reagents
and volumetric solutions?
6.19
9.55 Is a record maintained of standardization of volumetric solutions? 6.2 9.56 Are reagents for prolonged use labeled with 6.20
• date of the preparation?
• sign of the preparator?
9.57 Are unstable reagents labeled with 6.20 • expiry date?
• storage conditions?
9.58 Are volumetric solutions labeled with 6.20 • the last date of standardization?
• last current factor?
9.59 Are reference standards labeled with 6.21 • name and potency
• suppliers reference
• date of receipt
Compliance 1 2 3 Remarks EU-Guide
9.60 Are reference standards stored properly and under the control of a designated person?
9.61 Are animals used for testing of components, materials, or products
• quarantined before use?
• checked for suitability?
• Are records maintained showing the history of their use?
10 COMPLAINTS AND PRODUCT RECALLS 8
Complaints 8.1
10.1 Does a written complaint procedure exist? 8.2 10.2 Are product complaints carefully reviewed? 8.1 10.3 Is a person designated to handle complaints and to decide on
measures to be taken?
8.1
10.4 Is each complaint concerning a product recorded with all original details?
8.3
10.5 Are product complaints thoroughly investigated? 8.3 10.6 Is a responsible person of QC involved in the study? 8.3 10.7 Is it considered that other batches might be concerned
as well?
8.4
10.8 Are decisions and measures as a result recorded? 8.5 10.9 Is this record added to the corresponding batch documents? 8.5 10.10 Are the complaint records regularly revised with respect to
specific or recurring problems?
8.6
10.11 Are the authorities informed of serious quality problems with a product?
8.7
Recalls 8.8
10.12 Does a written recall procedure exist? 8.9 10.13 Is a person nominated responsible for the execution and
coordination of a recall?
8.8
10.14 Responsible person independent of the marketing and sales organization?
8.8
10.15 Are the competent authorities informed of an imminent recall? 8.11 10.16 Does the person responsible for a recall have access to the
distribution records?
8.12
10.17 Do the distribution records contain sufficient information on customers with
8.12
• addresses?
• phone numbers inside or outside working hours?
• batches and amounts delivered?
• medical samples?
10.18 Are recalled products stored separately in a secure area?
8.13
10.19 Is a final record made including a reconciliation between the delivered and recovered quantities?
8.14
10.20 Is the effectiveness of the arrangements for recalls checked critically from time to time?
8.15
11 SELF-INSPECTION 9
11.1 Does a self-inspection procedure exist which defines frequency and program?
9.1
11.2 Are self-inspections carried out to check compliance with GMP rules?
Compliance 1 2 3 Remarks EU-Guide
11.3 Are self-inspections conducted in an independent and detailed way?
9.2
by designated competent persons from the company or external experts?
11.4 Are self-inspections recorded? 9.3 11.5 Do reports contain 9.3
• the observations made during a self-inspection?
• proposals for corrective measures?
11.6 Are actions subsequently taken recorded? 9.3
12 CONTRACT MANUFACTURE AND ANALYSIS 7
12.1 Written contract between contract giver and contract acceptor available?
7.1
12.2 Are responsibilities and duties clearly defined? 7 12.3 All arrangements in accordance with the marketing
authorization of the product concerned?
7.2
The contract giver
12.4 Competence of the acceptor to carry out the work successful and according to GMP assessed?
7.3
12.5 Acceptor provided with all the information necessary to carry out the contract work?
7.4
12.6 Acceptor informed of safety aspects? 7.4 12.7 Conformance of products supplied by the acceptor ensured? 7.5 12.8 Product released by a qualified person on the acceptor’s side? 7.5
The contract acceptor
12.9 Does the acceptor have 7.6 • adequate premises and equipment?
• knowledge and experience?
• competent personnel?
• a manufacturing authorization?
12.10 Does the acceptor ensure that all products or materials delivered to him are suitable?
7.7
12.11 There must be no work passed to a third party without the permission of the giver.
7.8
12.12 If a third party is involved it must have the necessary manufacturing and analytical information.
7.8
The contract
12.13 Does the written contract specify the responsibilities? 7.10 12.14 Have technical aspects been drawn up by competent persons? 7.10 12.15 Release of material and check for compliance with the
marketing authorization defined?
7.11
12.16 Is defined who is responsible for 7.12 • purchasing of materials?
• IPC controls
• testing and release of materials?
• manufacturing and quality control?
• sampling?
• storage of batch documentation?
12.17 Are manufacturing, analytical, and distribution records available to the contract giver?
7.13
12.18 Contract permits the giver to visit the facilities of the acceptor?
Compliance 1 2 3 Remarks EU-Guide
12.19 In the case of contract analysis: Does the contract acceptor understand that he is subject to inspection by the competent authorities?
7.15
13 AUDIT OF SUPPLIERS 2.7
13.1 Supplier audits performed for • excipients?
• active substances?
• packaging material?
a1. Fulfilled or available; 2. partially fulfilled; 3. not fulfilled or not available.
GLOSSARY
Acceptance Criteria—Numerical limits, ranges, or other suit- able measures for acceptance of test results.
Active Pharmaceutical Ingredient (API) (or Drug Substance)—Any substance or mixture of sub- stances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
Air lock—An enclosed space with two or more doors, which is interposed between two or more rooms, for example, of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms when they need to be entered. An air lock is designed for use either by people or for goods and/or equipment.
API Starting Material—A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API Starting Material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in house. API Starting Mate- rials are normally of defined chemical properties and structure.
Authorized Person—The person recognized by the national regulatory authority as having the responsibility for ensuring that each batch of finished product has been manufactured, tested, and approved for release in com- pliance with the laws and regulations in force in that country.
Batch (or Lot)—A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval. A defined quantity of starting material, packaging material, or product processed in a single process or series of pro- cesses so that it is expected to be homogeneous. It may sometimes be necessary to divide a batch into a num- ber of subbatches, which are later brought together to form a final homogeneous batch. In the case of termi- nal sterilization, the batch size is determined by the capacity of the autoclave. In continuous manufacture, the batch must correspond to a defined fraction of the
production, characterized by its intended homogene- ity. The batch size can be defined either as a fixed quantity or as the amount produced in a fixed time interval.
Batch Number (or Lot Number)—A unique combination of numbers, letters, and/or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined. A distinctive combination of numbers and/or letters which uniquely identifies a batch on the labels, its batch records and corresponding certificates of analysis, and so on.
Batch Records—All documents associated with the manu- facture of a batch of bulk product or finished product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the final product.
Bioburden—The level and type (e.g., objectionable or not) of microorganisms that can be present in raw materials, API starting materials, intermediates, or APIs. Biobur- den should not be considered contamination unless the levels have been exceeded or defined objectionable or- ganisms have been detected.
Bulk Product—Any product that has completed all process- ing stages up to, but not including, final packaging.
Calibration—The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of mea- surements. The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (especially weighing), recording, and controlling, or the values represented by a material measure, and the cor- responding known values of a reference standard. Lim- its for acceptance of the results of measuring should be established.
Clean Area—An area with defined environmental control of particulate and microbial contamination, constructed, and used in such a way as to reduce the introduction, generation, and retention of contaminants within the area.
Computer System—A group of hardware components and associated software, designed and assembled to per- form a specific function or group of functions. A pro- cess or operation integrated with a computer system.
Consignment (or delivery)—The quantity of a pharmaceuti- cal(s), made by one manufacturer and supplied at one time in response to a particular request or order. A con- signment may comprise one or more packages or con- tainers and may include material belonging to more than one batch.
of a chemical or microbiological nature, or of foreign matter, into or on to a starting material or intermediate during production, sampling, packaging or repackag- ing, and storage or transport.
Contract Manufacturer—A manufacturer performing some aspect of manufacturing on behalf of the original man- ufacturer.
Critical—Describes a process step, process condition, test re- quirement, or other relevant parameter or item that must be controlled within predetermined criteria to en- sure that the API meets its specification.
Critical Operation—An operation in the manufacturing pro- cess that may cause variation in the quality of the phar- maceutical product.
Cross-Contamination—Contamination of a material or prod- uct with another material or product. Contamination of a starting material, intermediate product, or finished product with another starting material or product dur- ing production.
Deviation—Departure from an approved instruction or es- tablished standard.
Drug (Medicinal) Product—The dosage form in the final immediate packaging intended for marketing. (Reference Q1A).
Drug Substance—See Active Pharmaceutical Ingre- dient.
Expiry Date (or Expiration Date)—The date placed on the container/labels of an API designating the time during which the API is expected to remain within established shelf-life specifications if stored under defined condi- tions, and after which it should not be used.
Finished Product—A finished dosage form that has under- gone all stages of manufacture, including packaging in its final container and labeling.
Impurity—Any component present in the intermediate or API that is not the desired entity.
Impurity Profile—A description of the identified and uniden- tified impurities present in an API.
In-process Control—Checks performed during production in order to monitor and, if necessary, to adjust the pro- cess to ensure that the product conforms to its specifi- cations. The control of the environment or equipment may also be regarded as a part of in-process control.
Intermediate—A material produced during steps of the pro- cessing of an API that undergoes further molecular change or purification before it becomes an API. In- termediates may or may not be isolated. Partly pro- cessed product that must undergo further manufactur- ing steps before it becomes a bulk product.
Large-Volume Parenterals—Sterile solutions intended for parenteral application with a volume of 100 mL or more in one container of the finished dosage form.
Lot—See Batch.
Lot Number—See Batch Number.
Manufacture—All operations of receipt of materials, pro- duction, packaging, repackaging, labeling, relabeling, quality control, release, storage, and distribution of APIs and related controls.
Manufacturer—A company that carries out operations such as production, packaging, repackaging, labeling, and relabeling of pharmaceuticals.
Marketing Authorization (Product License, Registration Certificate)—A legal document issued by the compe- tent drug regulatory authority that establishes the de- tailed composition and formulation of the product and
of its ingredients and of the final product itself, and includes details of packaging, labeling, and shelf life.
Master Formula—A document or set of documents speci- fying the starting materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process con- trols.
Master Record—A document or set of documents that serve as a basis for the batch documentation (blank batch record).
Material—A general term used to denote raw materials (starting materials, reagents, solvents), process aids, in- termediates, APIs, and packaging and labeling materi- als.
Mother Liquor—The residual liquid which remains after the crystallization or isolation processes. A mother liquor may contain unreacted materials, intermediates, levels of the API, and/or impurities. It may be used for further processing.
Packaging—All operations, including filling and labeling, that a bulk product has to undergo in order to become a finished product. Filling of a sterile product under aseptic conditions or a product intended to be termi- nally sterilized, would not normally be regarded as part of packaging.
Packaging Material—Any material intended to protect an intermediate or API during storage and transport. Any material, including printed material, employed in the packaging of a pharmaceutical, but excluding any outer packaging used for transportation or shipment. Pack- aging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product.
Pharmaceutical Product—Any material or product intended for human or veterinary use presented in its finished dosage form or as a starting material for use in such a dosage form, that is subject to control by pharma- ceutical legislation in the exporting state and/or the importing state.
Procedure—A documented description of the operations to be performed, the precautions to be taken and mea- sures to be applied directly or indirectly related to the manufacture of an intermediate or API.
Process Aids—Materials, excluding solvents, used as an aid in the manufacture of an intermediate or API that do not themselves participate in a chemical or biological reaction (e.g. filter aid, activated carbon, and so on).
Process Control—See In-Process Control.
Production—All operations involved in the preparation of a pharmaceutical product, from receipt of materials, through processing, packaging and repackaging, and labeling and relabeling, to completion of the finished product.
Qualification—Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process val- idation.
Quality Assurance (QA)—The sum total of the organised arrangements made with the object of ensuring that all APIs are of the quality required for their intended use and that quality systems are maintained.
tions are met.
Quality Unit(s)—An organizational unit independent of production which fulfills both Quality Assurance and Quality Control responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.
Quarantine—The status of starting or packaging materials, intermediates, or bulk or finished products isolated physically or by other effective means while a deci- sion is awaited on their release, rejection, or reprocess- ing.
Raw Material—A general term used to denote starting ma- terials, reagents, and solvents intended for use in the production of intermediates or APIs.
Reconciliation—A comparison between the theoretical quantity and the actual quantity.
Recovery—The introduction of all or part of previous batches (or of redistilled solvents and similar products) of the required quality into another batch at a defined stage of manufacture. It includes the removal of impurities from waste to obtain a pure substance or the recovery of used materials for a separate use.
Reference Standard, Primary—A substance that has been shown by an extensive set of analytical tests to be au- thentic material that should be of high purity.
Reference Standard, Secondary—A substance of established quality and purity, as shown by comparison to a pri- mary reference standard, used as a reference standard for routine laboratory analysis.
Reprocessing—Subjecting all or part of a batch or lot of an in-process drug, bulk process intermediate (final bio- logical bulk intermediate) or bulk product of a single batch/lot to a previous step in the validated manufac- turing process due to failure to meet pre-determined specifications. Reprocessing procedures are foreseen as occasionally necessary for biological drugs and, in such cases, are validated and preapproved as part of the mar- keting authorization.
Retest Date—The date when a material should be reexam- ined to ensure that it is still suitable for use.
Reworking—Subjecting an in-process or bulk process inter- mediate (final biological bulk intermediate) or final product of a single batch to an alternate manufacturing process due to a failure to meet predetermined speci- fications. Reworking is an unexpected occurrence and is not preapproved as part of the marketing authoriza- tion.
Self-Contained Area—Premises which provide complete