Drains should be of adequate size and should be provided with an air break or a suitable device to prevent back-siphonage, when appropriate. Water used in the manufacture of APIs should be demonstrated to be suitable for its intended use.

Unless otherwise justified, process water should, at a minimum, meet World Health Organization WHO guidelines for drinking potable water quality. Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored with appropriate action limits.

Where the manufacturer of a nonsterile API either intends or claims that it is suitable for use in further processing to produce a sterile drug medicinal product, water used in the final isolation and purification steps should be monitored and controlled for total microbial counts, objectionable organisms, and endotoxins.

The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved e. Appropriate measures should be established and implemented to prevent cross-contamination from personnel and materials moving from one dedicated area to another.

Handling and storage of these highly toxic nonpharmaceutical materials should be separate from APIs. Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, and proper operations.

Sewage, refuse, and other waste e. Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition. Written procedures should be established assigning responsibility for sanitation and describing the cleaning schedules, methods, equipment, and materials to be used in cleaning buildings and facilities.

Equipment used in the manufacture of intermediates and APIs should be of appropriate design and adequate size, and suitably located for its intended use, cleaning, sanitation where appropriate , and maintenance. Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications.

Major equipment e. Any substances associated with the operation of equipment, such as lubricants, heating fluids or coolants, should not contact intermediates or APIs so as to alter the quality of APIs or intermediates beyond the official or other established specifications.

Any deviations from this practice should be evaluated to ensure that there are no detrimental effects on the material's fitness for use. Wherever possible, food grade lubricants and oils should be used.

Closed or contained equipment should be used whenever appropriate. Where open equipment is used, or equipment is opened, appropriate precautions should be taken to minimize the risk of contamination.

A set of current drawings should be maintained for equipment and critical installations e. Equipment Maintenance and Cleaning 5. Schedules and procedures including assignment of responsibility should be established for the preventative maintenance of equipment.

Written procedures should be established for cleaning equipment and its subsequent release for use in the manufacture of intermediates and APIs.

Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include:. Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or sterilized to prevent contamination or carry-over of a material that would alter the quality of the intermediate or API beyond the official or other established specifications.

Where equipment is assigned to continuous production or campaign production of successive batches of the same intermediate or API, equipment should be cleaned at appropriate intervals to prevent build-up and carry-over of contaminants e. Nondedicated equipment should be cleaned between production of different materials to prevent cross-contamination.

Acceptance criteria for residues and the choice of cleaning procedures and cleaning agents should be defined and justified. Equipment should be identified as to its contents and its cleanliness status by appropriate means.

Control, weighing, measuring, monitoring, and testing equipment critical for ensuring the quality of intermediates or APIs should be calibrated according to written procedures and an established schedule.

Equipment calibrations should be performed using standards traceable to certified standards, if they exist.

Deviations from approved standards of calibration on critical instruments should be investigated to determine if these could have had an effect on the quality of the intermediate s or API s manufactured using this equipment since the last successful calibration.

GMP-related computerized systems should be validated. The depth and scope of validation depends on the diversity, complexity, and criticality of the computerized application. Appropriate installation and operational qualifications should demonstrate the suitability of computer hardware and software to perform assigned tasks.

Commercially available software that has been qualified does not require the same level of testing. If an existing system was not validated at time of installation, a retrospective validation could be conducted if appropriate documentation is available.

Computerized systems should have sufficient controls to prevent unauthorized access or changes to data. There should be controls to prevent omissions in data e. There should be a record of any data change made, the previous entry, who made the change, and when the change was made. Written procedures should be available for the operation and maintenance of computerized systems.

Where critical data are being entered manually, there should be an additional check on the accuracy of the entry. This can be done by a second operator or by the system itself.

Incidents related to computerized systems that could affect the quality of intermediates or APIs or the reliability of records or test results should be recorded and investigated.

Changes to computerized systems should be made according to a change procedure and should be formally authorized, documented, and tested.

Records should be kept of all changes, including modifications and enhancements made to the hardware, software, and any other critical component of the system. These records should demonstrate that the system is maintained in a validated state. If system breakdowns or failures would result in the permanent loss of records, a back-up system should be provided.

A means of ensuring data protection should be established for all computerized systems. Documentation System and Specifications 6. All documents related to the manufacture of intermediates or APIs should be prepared, reviewed, approved, and distributed according to written procedures.

Such documents can be in paper or electronic form. The issuance, revision, superseding, and withdrawal of all documents should be controlled by maintaining revision histories.

A procedure should be established for retaining all appropriate documents e. 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. When entries are made in records, these should be made indelibly in spaces provided for such entries, directly after performing the activities, and should identify the person making the entry.

Corrections to entries should be dated and signed and leave the original entry still legible. During the retention period, originals or copies of records should be readily available at the establishment where the activities described in such records occurred. Records that can be promptly retrieved from another location by electronic or other means are acceptable.

Specifications, instructions, procedures, and records can be retained either as originals or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records. Where reduction techniques such as microfilming or electronic records are used, suitable retrieval equipment and a means to produce a hard copy should be readily available.

Specifications should be established and documented for raw materials, intermediates where necessary, APIs, and labeling and packaging materials. In addition, specifications may be appropriate for certain other materials, such as process aids, gaskets, or other materials used during the production of intermediates or APIs that could critically affect quality.

Acceptance criteria should be established and documented for in-process controls. Equipment Cleaning and Use Record 6. If equipment is dedicated to manufacturing one intermediate or API, individual equipment records are not necessary if batches of the intermediate or API follow in traceable sequence.

In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use can be part of the batch record or maintained separately. Records of Raw Materials, Intermediates, API Labeling and Packaging Materials 6.

Master Production Instructions Master Production and Control Records 6. To ensure uniformity from batch to batch, master production instructions for each intermediate and API should be prepared, dated, and signed by one person and independently checked, dated, and signed by a person in the quality unit s.

Batch Production Records Batch Production and Control Records 6. Batch production records should be prepared for each intermediate and API and should include complete information relating to the production and control of each batch. The batch production record should be checked before issuance to ensure that it is the correct version and a legible accurate reproduction of the appropriate master production instruction.

If the batch production record is produced from a separate part of the master document, that document should include a reference to the current master production instruction being used.

These records should be numbered with a unique batch or identification number, dated and signed when issued. In continuous production, the product code together with the date and time can serve as the unique identifier until the final number is allocated. Documentation of completion of each significant step in the batch production records batch production and control records should include:.

Written procedures should be established and followed for investigating critical deviations or the failure of a batch of intermediate or API to meet specifications. The investigation should extend to other batches that may have been associated with the specific failure or deviation.

Laboratory control records should include complete data derived from all tests conducted to ensure compliance with established specifications and standards, including examinations and assays, as follows:.

Batch Production Record Review 6. Written procedures should be established and followed for the review and approval of batch production and laboratory control records, including packaging and labeling, to determine compliance of the intermediate or API with established specifications before a batch is released or distributed.

Batch production and laboratory control records of critical process steps should be reviewed and approved by the quality unit s before an API batch is released or distributed. Production and laboratory control records of noncritical process steps can be reviewed by qualified production personnel or other units following procedures approved by the quality unit s.

All deviation, investigation, and OOS reports should be reviewed as part of the batch record review before the batch is released. The quality unit s can delegate to the production unit the responsibility and authority for release of intermediates, except for those shipped outside the control of the manufacturing company.

There should be written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials.

Materials should be purchased against an agreed specification, from a supplier, or suppliers, approved by the quality unit s. Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control. Upon receipt and before acceptance, each container or grouping of containers of materials should be examined visually for correct labeling including correlation between the name used by the supplier and the in-house name, if these are different , container damage, broken seals and evidence of tampering or contamination.

Materials should be held under quarantine until they have been sampled, examined, or tested, as appropriate, and released for use. Before incoming materials are mixed with existing stocks e.

Procedures should be available to prevent discharging incoming materials wrongly into the existing stock. If bulk deliveries are made in nondedicated tankers, there should be assurance of no cross-contamination from the tanker.

Means of providing this assurance could include one or more of the following:. Large storage containers and their attendant manifolds, filling, and discharge lines should be appropriately identified. Each container or grouping of containers batches of materials should be assigned and identified with a distinctive code, batch, or receipt number.

This number should be used in recording the disposition of each batch. A system should be in place to identify the status of each batch. Sampling and Testing of Incoming Production Materials 7. At least one test to verify the identity of each batch of material should be conducted, with the exception of the materials described below.

A supplier's certificate of analysis can be used in place of performing other tests, provided that the manufacturer has a system in place to evaluate suppliers. Supplier approval should include an evaluation that provides adequate evidence e.

Complete analyses should be conducted on at least three batches before reducing in-house testing. However, as a minimum, a complete analysis should be performed at appropriate intervals and compared with the certificates of analysis.

Reliability of certificates of analysis should be checked at regular intervals. Processing aids, hazardous or highly toxic raw materials, other special materials, or materials transferred to another unit within the company's control do not need to be tested if the manufacturer's certificate of analysis is obtained, showing that these raw materials conform to established specifications.

Visual examination of containers, labels, and recording of batch numbers should help in establishing the identity of these materials. The lack of on-site testing for these materials should be justified and documented. Samples should be representative of the batch of material from which they are taken.

Sampling methods should specify the number of containers to be sampled, which part of the container to sample, and the amount of material to be taken from each container. The number of containers to sample and the sample size should be based on a sampling plan that takes into consideration the criticality of the material, material variability, past quality history of the supplier, and the quantity needed for analysis.

Sampling should be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials. Containers from which samples are withdrawn should be opened carefully and subsequently reclosed.

They should be marked to indicate that a sample has been taken. Materials should be handled and stored in a manner to prevent degradation, contamination, and cross-contamination.

Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when appropriate, suitably spaced to permit cleaning and inspection. Materials should be stored under conditions and for a period that have no adverse effect on their quality, and should normally be controlled so that the oldest stock is used first.

Certain materials in suitable containers can be stored outdoors, provided identifying labels remain legible and containers are appropriately cleaned before opening and use. Rejected materials should be identified and controlled under a quarantine system designed to prevent their unauthorized use in manufacturing.

Materials should be re-evaluated, as appropriate, to determine their suitability for use e. Raw materials for intermediate and API manufacturing should be weighed or measured under appropriate conditions that do not affect their suitability for use.

Weighing and measuring devices should be of suitable accuracy for the intended use. If a material is subdivided for later use in production operations, the container receiving the material should be suitable and should be so identified that the following information is available:.

Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control. Prior to use, production personnel should verify that the materials are those specified in the batch record for the intended intermediate or API.

Actual yields should be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges should be established based on previous laboratory, pilot scale, or manufacturing data.

Deviations in yield associated with critical process steps should be investigated to determine their impact or potential impact on the resulting quality of affected batches.

The processing status of major units of equipment should be indicated either on the individual units of equipment or by appropriate documentation, computer control systems, or alternative means. Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use.

If time limits are specified in the master production instruction see 6. Deviations should be documented and evaluated. Time limits may be inappropriate when processing to a target value e.

Intermediates held for further processing should be stored under appropriate conditions to ensure their suitability for use. In-process Sampling and Controls 8.

Written procedures should be established to monitor the progress and control the performance of processing steps that cause variability in the quality characteristics of intermediates and APIs. In-process controls and their acceptance criteria should be defined based on the information gained during the developmental stage or from historical data.

The acceptance criteria and type and extent of testing can depend on the nature of the intermediate or API being manufactured, the reaction or process step being conducted, and the degree to which the process introduces variability in the product's quality.

Less stringent in-process controls may be appropriate in early processing steps, whereas tighter controls may be appropriate for later processing steps e. Critical in-process controls and critical process monitoring , including control points and methods, should be stated in writing and approved by the quality unit s.

In-process controls can be performed by qualified production department personnel and the process adjusted without prior quality unit s approval if the adjustments are made within pre-established limits approved by the quality unit s.

All tests and results should be fully documented as part of the batch record. Written procedures should describe the sampling methods for in-process materials, intermediates, and APIs.

Sampling plans and procedures should be based on scientifically sound sampling practices. In-process sampling should be conducted using procedures designed to prevent contamination of the sampled material and other intermediates or APIs.

Procedures should be established to ensure the integrity of samples after collection. Blending Batches of Intermediates or APIs 8. For the purpose of this document, blending is defined as the process of combining materials within the same specification to produce a homogeneous intermediate or API.

In-process mixing of fractions from single batches e. Out-of-specification batches should not be blended with other batches for the purpose of meeting specifications.

Each batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending. Blending processes should be adequately controlled and documented, and the blended batch should be tested for conformance to established specifications, where appropriate.

The batch record of the blending process should allow traceability back to the individual batches that make up the blend. Where physical attributes of the API are critical e. Validation should include testing of critical attributes e.

If the blending could adversely affect stability, stability testing of the final blended batches should be performed. The expiry or retest date of the blended batch should be based on the manufacturing date of the oldest tailings or batch in the blend.

Residual materials can be carried over into successive batches of the same intermediate or API if there is adequate control. Examples include residue adhering to the wall of a micronizer, residual layer of damp crystals remaining in a centrifuge bowl after discharge, and incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process.

Such carryover should not result in the carryover of degradants or microbial contamination that may adversely alter the established API impurity profile. Production operations should be conducted in a manner that prevents contamination of intermediates or APIs by other materials.

Packaging and labeling materials should conform to established specifications. Those that do not comply with such specifications should be rejected to prevent their use in operations for which they are unsuitable. Records should be maintained for each shipment of labels and packaging materials showing receipt, examination, or testing, and whether accepted or rejected.

Containers should provide adequate protection against deterioration or contamination of the intermediate or API that may occur during transportation and recommended storage. Containers should be clean and, where indicated by the nature of the intermediate or API, sanitized to ensure that they are suitable for their intended use.

These containers should not be reactive, additive, or absorptive so as to alter the quality of the intermediate or API beyond the specified limits.

If containers are reused, they should be cleaned in accordance with documented procedures, and all previous labels should be removed or defaced. Procedures should be established to reconcile the quantities of labels issued, used, and returned and to evaluate discrepancies found between the number of containers labeled and the number of labels issued.

Such discrepancies should be investigated, and the investigation should be approved by the quality unit s. All excess labels bearing batch numbers or other batch-related printing should be destroyed. Returned labels should be maintained and stored in a manner that prevents mix-ups and provides proper identification.

Printing devices used to print labels for packaging operations should be controlled to ensure that all imprinting conforms to the print specified in the batch production record. Printed labels issued for a batch should be carefully examined for proper identity and conformity to specifications in the master production record.

The results of this examination should be documented. Packaging and Labeling Operations 9. There should be documented procedures designed to ensure that correct packaging materials and labels are used. Labeling operations should be designed to prevent mix-ups. There should be physical or spatial separation from operations involving other intermediates or APIs.

Labels used on containers of intermediates or APIs should indicate the name or identifying code, batch number, and storage conditions when such information is critical to ensure the quality of intermediate or API. If the intermediate or API is intended to be transferred outside the control of the manufacturer's material management system, the name and address of the manufacturer, quantity of contents, special transport conditions, and any special legal requirements should also be included on the label.

For intermediates or APIs with an expiry date, the expiry date should be indicated on the label and certificate of analysis. Packaging and labeling facilities should be inspected immediately before use to ensure that all materials not needed for the next packaging operation have been removed.

This examination should be documented in the batch production records, the facility log, or other documentation system. Packaged and labeled intermediates or APIs should be examined to ensure that containers and packages in the batch have the correct label.

This examination should be part of the packaging operation. Results of these examinations should be recorded in the batch production or control records.

Intermediate or API containers that are transported outside of the manufacturer's control should be sealed in a manner such that, if the seal is breached or missing, the recipient will be alerted to the possibility that the contents may have been altered.

Facilities should be available for the storage of all materials under appropriate conditions e. Records should be maintained of these conditions if they are critical for the maintenance of material characteristics.

Unless there is an alternative system to prevent the unintentional or unauthorized use of quarantined, rejected, returned, or recalled materials, separate storage areas should be assigned for their temporary storage until the decision as to their future use has been made.

APIs and intermediates should only be released for distribution to third parties after they have been released by the quality unit s. APIs and intermediates can be transferred under quarantine to another unit under the company's control when authorized by the quality unit s and if appropriate controls and documentation are in place.

APIs and intermediates should be transported in a manner that does not adversely affect their quality. Special transport or storage conditions for an API or intermediate should be stated on the label. The manufacturer should ensure that the contract acceptor contractor for transportation of the API or intermediate knows and follows the appropriate transport and storage conditions.

There should be documented procedures describing sampling, testing, approval, or rejection of materials and recording and storage of laboratory data. Laboratory records should be maintained in accordance with Section 6.

Specifications, sampling plans, and test procedures, including changes to them, should be drafted by the appropriate organizational unit and reviewed and approved by the quality unit s.

Appropriate specifications should be established for APIs in accordance with accepted standards and consistent with the manufacturing process. The specifications should include control of impurities e.

If the API has a specification for microbiological purity, appropriate action limits for total microbial counts and objectionable organisms should be established and met. If the API has a specification for endotoxins, appropriate action limits should be established and met. Laboratory controls should be followed and documented at the time of performance.

Any departures from the above-described procedures should be documented and explained. Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should include analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions.

Reagents and standard solutions should be prepared and labeled following written procedures. Use by dates should be applied, as appropriate, for analytical reagents or standard solutions.

Primary reference standards should be obtained, as appropriate, for the manufacture of APIs. The source of each primary reference standard should be documented.

Records should be maintained of each primary reference standard's storage and use in accordance with the supplier's recommendations. Primary reference standards obtained from an officially recognized source are normally used without testing if stored under conditions consistent with the supplier's recommendations.

Where a primary reference standard is not available from an officially recognized source, an in-house primary standard should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained.

Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard.

Each batch of secondary reference standard should be periodically requalified in accordance with a written protocol. Testing of Intermediates and APIs For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications. An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API.

The impurity profile should include the identity or some qualitative analytical designation e. The impurity profile is normally dependent upon the production process and origin of the API.

Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin. Biotechnology considerations are covered in ICH guidance Q6B. The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.

Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified. Validation of Analytical Procedures - See Section Authentic certificates of analysis should be issued for each batch of intermediate or API on request.

Information on the name of the intermediate or API including, where appropriate, its grade, the batch number, and the date of release should be provided on the certificate of analysis.

For intermediates or APIs with an expiry date, the expiry date should be provided on the label and certificate of analysis.

The certificate should list each test performed in accordance with compendial or customer requirements, including the acceptance limits, and the numerical results obtained if test results are numerical.

Certificates should be dated and signed by authorized personnel of the quality unit s and should show the name, address, and telephone number of the original manufacturer. They should also contain a reference to the name and address of the original manufacturer and to the original batch certificate, a copy of which should be attached.

A documented, on-going testing program should be established to monitor the stability characteristics of APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates. Stability samples should be stored in containers that simulate the market container.

For example, if the API is marketed in bags within fiber drums, stability samples can be packaged in bags of the same material and in small-scale drums of similar or identical material composition to the market drums. Normally, the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date.

However, where data from previous studies show that the API is expected to remain stable for at least 2 years, fewer than three batches can be used. Thereafter, at least one batch per year of API manufactured unless none is produced that year should be added to the stability monitoring program and tested at least annually to confirm the stability.

For APIs with short shelf-lives, testing should be done more frequently. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals e. Where appropriate, the stability storage conditions should be consistent with the ICH guidances on stability.

When an intermediate is intended to be transferred outside the control of the manufacturer's material management system and an expiry or retest date is assigned, supporting stability information should be available e.

An API expiry or retest date should be based on an evaluation of data derived from stability studies. Common practice is to use a retest date, not an expiration date. Preliminary API expiry or retest dates can be based on pilot scale batches if 1 the pilot batches employ a method of manufacture and procedure that simulates the final process to be used on a commercial manufacturing scale and 2 the quality of the API represents the material to be made on a commercial scale.

The packaging and holding of reserve samples is for the purpose of potential future evaluation of the quality of batches of API and not for future stability testing purposes.

Appropriately identified reserve samples of each API batch should be retained for 1 year after the expiry date of the batch assigned by the manufacturer, or for 3 years after distribution of the batch, whichever is longer.

For APIs with retest dates, similar reserve samples should be retained for 3 years after the batch is completely distributed by the manufacturer. The reserve sample should be stored in the same packaging system in which the API is stored or in one that is equivalent to or more protective than the marketed packaging system.

Sufficient quantities should be retained to conduct at least two full compendial analyses or, when there is no pharmacopoeial monograph, two full specification analyses. The company's overall policy, intentions, and approach to validation, including the validation of production processes, cleaning procedures, analytical methods, in-process control test procedures, computerized systems, and persons responsible for design, review, approval, and documentation of each validation phase, should be documented.

This should include:. Validation should extend to those operations determined to be critical to the quality and purity of the API. A written validation protocol should be established that specifies how validation of a particular process will be conducted.

The protocol should be reviewed and approved by the quality unit s and other designated units. The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted e. A validation report that cross-references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.

Before initiating process validation activities, appropriate qualification of critical equipment and ancillary systems should be completed. Qualification is usually carried out by conducting the following activities, individually or combined:. Design Qualification DQ : documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose.

Operational Qualification OQ : documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges. Performance Qualification PQ : documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications.

Approaches to Process Validation Process Validation PV is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.

There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches can be used. These approaches and their applicability are discussed here.

Prospective validation should normally be performed for all API processes as defined in Prospective validation of an API process should be completed before the commercial distribution of the final drug product manufactured from that API.

Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently, or API batches are produced by a validated process that has been modified.

Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches.

An exception can be made for retrospective validation of well-established processes that have been used without significant changes to API quality due to changes in raw materials, equipment, systems, facilities, or the production process. This validation approach may be used where:. Batches selected for retrospective validation should be representative of all batches produced during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency.

Retained samples can be tested to obtain data to retrospectively validate the process. The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process e.

For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.

Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.

Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.

Periodic Review of Validated Systems Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.

Cleaning procedures should normally be validated. In general, cleaning validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality.

For example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps. Validation of cleaning procedures should reflect actual equipment usage patterns.

If various APIs or intermediates are manufactured in the same equipment and the equipment is cleaned by the same process, a representative intermediate or API can be selected for cleaning validation. This selection should be based on the solubility and difficulty of cleaning and the calculation of residue limits based on potency, toxicity, and stability.

The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods.

The protocol should also indicate the type of samples to be obtained and how they are collected and labeled. Sampling should include swabbing, rinsing, or alternative methods e. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning.

Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.

The method's attainable recovery level should be established. Residue limits should be practical, achievable, verifiable, and based on the most deleterious residue.

Limits can be established based on the minimum known pharmacological, toxicological, or physiological activity of the API or its most deleterious component. Cleaning procedures should be monitored at appropriate intervals after validation to ensure that these procedures are effective when used during routine production.

Equipment cleanliness can be monitored by analytical testing and visual examination, where feasible. Validation of Analytical Methods Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognized standard reference. When making a solution, the manufacturer must first decide what degree of chemical purity is needed based on the intended use.

ACS, Reagent, and USP-NF grades are typically equivalent and interchangeable but, even so, appropriateness should always be confirmed before application.

This can be done by reviewing the applicable regulatory requirements. Lab, purified, and technical grades have their own uses. For example, lab-grade chemicals, because of their low cost and good chemical purity, are used widely in educational applications, such as teaching laboratories at both the secondary school and college levels; however, lab-grade chemicals would not be appropriate for use in the quality control laboratory of a pharmaceutical or medical device manufacturer.

ACS-, USP-, or reagent-grade chemicals should be applied in this setting, because they have fewer impurities that could ultimately impact patients taking the drugs made with those chemicals.

With seven different and inequivalent types of chemical purity grades, it is crucial to understand how they can impact products. Similarly, using a higher-purity grade when not required could result in unnecessary costs. Add in the increased regulatory scrutiny and it becomes even more important to have a complete understanding of the components that your process requires.

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Does not have a strict percentage of purity but is still considered an upper-level intermediate quality chemical. Can be used for general procedures and within the food and beverage, pharmaceutical, and medical industries.

USP grade: Meets or exceeds the requirements of the United States Pharmacopeia USP and is equivalent to ACS grade. Considered top-rank quality for laboratory experimentation. below are the magnesium products offered by Garrison Minerals in the pharmaceutical, food, NF, ACS and USP grades.

High Purity grade: Chemicals that are of high quality while having no published standards. Purified grade: Also called pure or practical grade , which is a lower level of good quality that meets no official standard. It can be used for educational purposes, but is not pure enough to be offered for food, drug, or medicinal use.

Laboratory grade: Has the lowest of purity and is similar to that of purified grade. The laboratory grade does not have a strict percentage of purity but is still considered high quality.

Its low cost and solid chemical purity make it most suitable for educational purposes, but is not pure enough to be offered for food, drug, or medicinal use. Reagent grade: Equal to that of ACS grade.

In addition, it is suitable for analytical work and general laboratory use. Your friends at Garrison Minerals have the knowledge and expertise to answer any chemical grade questions you may have.

All of our products have technical data sheets and certificates of analysis that assist in the identification of material grades.

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Some materials can increase the risk of introducing adventitious agents into the process and final product. Thus, raw material qualification is extremely important in ensuring process control and final product quality.

Qualification programs rely on risk assessment strategies that may include testing raw materials before they are introduced into manufacturing. This article describes some of the challenges involved in qualifying raw materials for use in biologics production, and how quality standards may evolve to support biologics manufacturing.

With biopharmaceuticals, however, this definition can be expanded to include other materials that are added to the manufacturing process, or that may come in contact with the active ingredient, including process materials such as buffer and media, selection devices, ancillary materials, packaging materials, and excipients.

Each of these types of materials must be qualified before manufacturing can safely begin. Quality by design QbD principles call for the use of systematic approaches to development, starting with predefined objectives and an emphasis on product and process understanding and process control.

This approach underscores the importance of raw materials and all the components of the manufacturing processes. In addition to regulations and guidances, standards developed by the United States Pharmacopeia USP and other pharmacopeias can help biopharmaceutical manufacturers meet requirements.

The use of raw materials that have been manufactured in a GMP-compliant environment provides assurance that the processes used to make the materials are reproducible and that the quality of final products is controlled.

In such cases, changes to the process cannot be implemented without assessing their impact on the finished product. When raw materials are procured from commercial, non-GMP compliant sources, however, the risks of manufacturing failure increase.

In this type of situation, raw material specifications may change without an assessment of their impact on finished product quality. In addition, specifications for non-GMP-compliant raw materials are often wider than would be acceptable in a GMP-compliant environment.

It is important to use formal programs to qualify the raw materials used in biopharmaceutical manufacturing to ensure the safety of finished products. For biologics, raw material qualification can be a lengthy, multi-step process.

The technical information e. But the CoA alone may not be sufficient. Risk-based assessment can be used to determine the criticality of the raw material. The level of risk will determine the level of testing required, beyond the information found in the CoA.

Generally, a raw material that is used in large quantities in the downstream process will pose a higher level of risk than one that is used in small amounts in an upstream process.

Similarly, a material that is used in steps of the process with long holding times will pose a greater risk than one used where there are shorter holding times. The use of animal- or human- derived materials presents the additional risk of introducing adventitious agents or communicable diseases into the process.

When these materials are used in a process, screening for potential contaminants is a crucial element of the control strategy. The risk-based approach will depend on the potential for raw materials to remain present, at trace levels, in finished product.

It is also important to study the impact of the raw material on the development and manufacture of biological drug substances, as per ICH Q11 2. The risk-based categorization takes into account the initial intended use of these materials e.

Also considered are:. Table I shows the criteria that define the level of risk for these four tiers of raw materials used in the manufacturing of cell therapy products and biological manufacturing in general.

Intended for use as licensed drugs, biologics, or medical devices. Suitability for use as a manufacturing component is required because the formulation, stability profile, and other quality aspects of these materials may change once the material has been introduced in the manufacturing process.

Intended to be used as ancillary materials. These materials are well-characterized and produced under quality systems well-suited for biological manufacturing, but the materials are not licensed medical products.

Many are produced specifically for use in the manufacture of biological products. Research-grade materials not intended for use in biological manufacturing. Sometimes, these products are approved by regulatory agencies as part of an in vitro diagnostic device. Tier 3 requires more qualification than Tier 1 or Tier 2 materials.

Materials produced as industrial or research-grade materials and may contain harmful impurities. They may also contain animal- or human-derived components with potential contaminants.

This tier requires extensive qualification before use as component in biological product manufacturing. These efforts also resulted in reference standards that support the test. An example of this work, and the hierarchy of approach, is presented in Figure 1.

Figure 1. Standards for raw and ancillary materials: from general to specific. All figures are courtesy of the author. These reference standards may be used as calibrators as well as critical materials to develop residual testing for these materials and control the level of their removal from finished therapeutic products.

Standards for the raw and ancillary materials used in pharmaceutical and biopharmaceutical manufacturing have always been included in. USP—National Formulary USP—NF , in the form of monographs and supported by reference standards.

Examples of these standards include some for inorganic salts, vitamins, amino acids, carbohydrates, and other buffers and components of raw materials.