The FDA Drug Product Surveillance Program
B. Inspection Planning
VI. REGULATORY/ADMINISTRATIVE STRATEGY
Inspection findings that demonstrate that a firm is not oper- ating in a state of control may be used as evidence for taking appropriate advisory, administrative, or judicial actions.
When the management of the firm is unwilling or un- able to provide adequate corrective actions in an appropriate time frame, formal agency regulatory actions will be recom- mended that are designed to meet the situation encountered. When deciding the type of action to recommend, the initial decision should be based on the seriousness of the problem and the most effective way to protect consumers. Outstanding instructions in the Regulatory Procedures Manual (RPM) should be followed.
The endorsement to the inspection report should point out the actions that have been taken or will be taken and when. All deficiencies noted in inspections/audits under this program must be addressed by stating the firm’s corrective actions, accomplished or projected, for each as established in the discussion with management at the close of the inspection. All corrective action approaches in domestic firms are monitored and managed by the District Offices. The approaches may range from shutdown of operations, re- call of products, conducting testing programs, develop- ment of new procedures, modifications of plants and equipment, to simple immediate corrections of conditions. CDER/DMPQ/CMGB/HFD-325 will assist District Offices as requested.
An inspection report that documents that one or more systems is/are out of control should be classified as OAI. Dis- trict Offices may issue Warning Letters per RPM to warn firms of violations, to solicit voluntary corrections, and to provide for the initial phase of formal agency regulatory actions.
Issuance of a Warning Letter or taking other regulatory actions pursuant to a surveillance inspection (other than a For Cause Inspection) should result in the classification of all profile classes as unacceptable. Also, the inspection find- ings will be used as the basis for updating profile classes in FACTS.
The FDA laboratory tests that demonstrate the effects of absent or inadequate cGMPs are strong evidence for support- ing regulatory actions. Such evidence development should be considered as an inspection progresses and deficiencies are found; however, the lack of violative physical samples is not a barrier to pursuing regulatory or administrative action, pro- vided that cGMP deficiencies have been well documented. Likewise, physical samples found to be in compliance are not a barrier to pursuing action under cGMP charges.
Evidence to support significant deficiencies or a trend of deficiencies within a system covered could demonstrate the failure of a system and should result in consideration of the issuance of a Warning Letter or other regulatory action by the District. When deciding the type of action to recom- mend, the initial decision should be based on the seriousness or the frequency of the problem. Examples include the fol- lowing:
Quality System
1. Pattern of failure to review/approve procedures 2. Pattern of failure to document execution of operations
as required
3. Pattern of failure to review documentation
4. Pattern of failure to conduct investigations and resolve discrepancies/failures/deviations/complaints 5. Pattern of failure to assess other systems to assure com-
pliance with GMP and SOPs Facilities and Equipment
1. Contamination with filth, objectionable microorgan- isms, toxic chemicals or other drug chemicals, or a rea- sonable potential for contamination, with demonstrated
16 Handbook of Pharmaceutical Manufacturing Formulations: Liquid Products
avenues of contamination, such as airborne or through unclean equipment
2. Pattern of failure to validate cleaning procedures for nondedicated equipment; lack of demonstration of ef- fectiveness of cleaning for dedicated equipment 3. Pattern of failure to document investigation of discrep-
ancies
4. Pattern of failure to establish/follow a control system for implementing changes in the equipment
5. Pattern of failure to qualify equipment, including com- puters
Materials System
1. Release of materials for use or distribution that do not conform to established specifications
2. Pattern of failure to conduct one specific identity test for components
3. Pattern of failure to document investigation of discrep- ancies
4. Pattern of failure to establish/follow a control system for implementing changes in the materials handling op- erations
5. Lack of validation of water systems as required depend- ing upon the intended use of the water
6. Lack of validation of computerized processes Production System
1. Pattern of failure to establish/follow a control system for implementing changes in the production system op- erations
2. Pattern of failure to document investigation of discrep- ancies
3. Lack of process validation
4. Lack of validation of computerized processes
5. Pattern of incomplete or missing batch production records
6. Pattern of nonconformance to established in-process controls, tests, and specifications
Packaging and Labeling
1. Pattern of failure to establish/follow a control system for implementing changes in the packaging or labeling operations
2. Pattern of failure to document investigation of discrep- ancies
3. Lack of validation of computerized processes
4. Lack of control of packaging and labeling operations that may introduce a potential for mislabeling
5. Lack of packaging validation Laboratory Control System
1. Pattern of failure to establish/follow a control system for implementing changes in the laboratory operations 2. Pattern of failure to document investigation of discrep-
ancies
3. Lack of validation of computerized and/or automated processes
4. Pattern of inadequate sampling practices 5. Lack of validated analytical methods
6. Pattern of failure to follow approved analytical proce- dures
7. Pattern of failure to follow an adequate OOS procedure 8. Pattern of failure to retain raw data
9. Lack of stability indicating methods
10. Pattern of failure to follow stability programs
Follow-up to a Warning Letter or other significant reg- ulatory action because of an abbreviated inspection should warrant full inspection coverage as defined in this program.
GLOSSARY
Acceptance Criteria—Numerical limits, ranges, or other suit- able measures for acceptance of test results.
Active Pharmaceutical Ingredient (API) (or Drug Sub-
stance)—Any substance or mixture of substances in- tended to be used in the manufacture of a drug (medic- inal) product and that, when used in the production of a drug, becomes an active ingredient of the drug prod- uct. Such substances are intended to furnish pharma- cological 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.
Airlock—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 airlock 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 sub-batches, 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, etc.
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
The FDA Drug Product Surveillance Program 17
of all circumstances pertinent to the quality of the final product.
Bioburden—The level and type (e.g., objectionable or not) of micro-organisms 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 pharmaceu- tical(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.
Contamination—The undesired introduction of impurities of a chemical or microbiological nature, or of foreign mat- ter, into or onto a raw material, intermediate, or API during production, sampling, packaging or repackag- ing, 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 im- mediate packaging intended for marketing. (Reference Q1A)
Drug Substance—See Active Pharmaceutical Ingredient
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.
Fnished 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 spec- ifications. The control of the environment or equip- ment 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 com- petent drug regulatory authority that establishes the detailed composition and formulation of the product and the pharmacopoeial or other recognized specifi- cations of its ingredients and of the final product it- self, 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 controls.
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, intermediates, APIs and packaging and labeling ma- terials.
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 be- come a finished product. Filling of a sterile product under aseptic conditions or a product intended to be
18 Handbook of Pharmaceutical Manufacturing Formulations: Liquid Products
terminally 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, etc).
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, la- beling 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 re- sults. Qualification is part of validation, but the individ- ual qualification steps alone do not constitute process validation.
Quality Assurance (QA)—The sum total of the organized 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.
Quality Control (QC)—Checking or testing that specifica- tions are met.
Quality Unit(s)—An organizational unit independent of pro- duction 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 materi- als, intermediates, or bulk or finished products iso- lated physically or by other effective means while a decision is awaited on their release, rejection, or reprocessing.
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 prod- ucts) of the required quality into another batch at a defined stage of manufacture. It includes the re- moval of impurities from waste to obtain a pure sub- stance 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 manu- facturing process due to failure to meet predetermined 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 specifi- cations. Reworking is an unexpected occurrence and is not pre-approved as part of the marketing authoriza- tion.
Self-Contained Area—Premises which provide complete and total separation of all aspects of an operation, including personnel and equipment movement, with well-established procedures, controls, and monitoring. This includes physical barriers as well as separate air- handling systems, but does not necessarily imply two distinct and separate buildings.
Signature (Signed)—See definition for signed
Signed (Signature)—The record of the individual who per- formed a particular action or review. This record can