Good Manufacturing Practice Guide for Active Pharmaceutical Ingredient

2.10

Quality should be the responsibility of all persons involved in manufacturing.

2.11

Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.

2.12

The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and documented.

2.13

There should be a quality unit(s) that is independent of production and that fulfills both quality assurance (QA) and quality control (QC) 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.

2.14

The persons authorised to release intermediates and APIs should be specified.

2.15

All quality related activities should be recorded at the time they are performed.

2.16

Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented.

2.17

No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g. release under quarantine as described in Section 10.20 or the use of raw materials or intermediates pending completion of evaluation).

2.18

Procedures should exist for notifying responsible management in a timely manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality related complaints, recalls, regulatory actions, etc.).

3.10

There should be an adequate number of personnel qualified by appropriate education, training and/or experience to perform and supervise the manufacture of intermediates and APIs.

3.11

The responsibilities of all personnel engaged in the manufacture of intermediates and APIs should be specified in writing.

3.12

Training should be regularly conducted by qualified individuals and should cover, at a minimum, the particular operations that the employee performs and GMP as it relates to the employee's functions. Records of training should be maintained. Training should be periodically assessed.

4.10

Buildings and facilities used in the manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance, and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimize potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants as appropriate.

4.11

Buildings and facilities should have adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination.

4.12

Where the equipment itself (e.g., closed or contained systems) provides adequate protection of the material, such equipment can be located outdoors.

4.13

The flow of materials and personnel through the building or facilities should be designed to prevent mix-ups or contamination.

4.14

There should be defined areas or other control systems for the following activities:

4.15

Adequate, clean washing and toilet facilities should be provided for personnel. These washing facilities should be equipped with hot and cold water as appropriate, soap or detergent, air driers or single service towels. The washing and toilet facilities should be separate from, but easily accessible to, manufacturing areas. Adequate facilities for showering and/or changing clothes should be provided, when appropriate.

4.16

Laboratory areas/operations should normally be separated from production areas. Some laboratory areas, in particular those used for in-process controls, can be located in production areas, provided the operations of the production process do not adversely affect the accuracy of the laboratory measurements, and the laboratory and its operations do not adversely affect the production process or intermediate or API.

5.10

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, sanitization (where appropriate), and maintenance.

5.11

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.

5.12

Production equipment should only be used within its qualified operating range.

5.13

Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified.

5.14

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 their quality beyond the official or other established specifications. Any deviations from this should be evaluated to ensure that there are no detrimental effects upon the fitness for purpose of the material. Wherever possible, food grade lubricants and oils should be used.

5.15

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.

5.16

A set of current drawings should be maintained for equipment and critical installations (e.g., instrumentation and utility systems).

6.10

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.

6.11

The issuance, revision, superseding and withdrawal of all documents should be controlled with maintenance of revision histories.

6.12

A procedure should be established for retaining all appropriate documents (e.g., development history reports, scale-up reports, technical transfer reports, process validation reports, training records, production records, control records, and distribution records). The retention periods for these documents should be specified.

6.13

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.

6.14

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 readable.

6.15

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.

6.16

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.

6.17

Specifications should be established and documented for raw materials, intermediates where necessary, APIs, and labelling 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 impact on quality. Acceptance criteria should be established and documented for in-process controls.

6.18

If electronic signatures are used on documents, they should be authenticated and secure.

7.10

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

7.11

Manufacturers of intermediates and/or APIs should have a system for evaluating the suppliers of critical materials.

7.12

Materials should be purchased against an agreed specification, from a supplier or suppliers approved by the quality unit(s).

7.13

If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.

7.14

Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control.

8.10

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.

8.11

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:

- Material name and/or item code;
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- Receiving or control number;
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- Weight or measure of material in the new container; and
‍
- Re-evaluation or retest date if appropriate.

8.12

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.

8.13

Other critical activities should be witnessed or subjected to an equivalent control.

8.14

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.

8.15

Any deviation should be documented and explained. Any critical deviation should be investigated.

8.16

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.

8.17

Materials to be reprocessed or reworked should be appropriately controlled to prevent unauthorized use.

9.10

There should be written procedures describing the receipt, identification, quarantine, sampling, examination and/or testing and release, and handling of packaging and labelling materials.

9.11

Packaging and labelling 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.

9.12

Records should be maintained for each shipment of labels and packaging materials showing receipt, examination, or testing, and whether accepted or rejected.

9.20

Containers should provide adequate protection against deterioration or contamination of the intermediate or API that may occur during transportation and recommended storage.

9.21

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.

9.22

If containers are re-used, they should be cleaned in accordance with documented procedures and all previous labels should be removed or defaced.

9.30

Access to the label storage areas should be limited to authorised personnel.

9.31

Procedures should be used to reconcile the quantities of labels issued, used, and returned and to evaluate discrepancies found between the number of containers labelled and the number of labels issued. Such discrepancies should be investigated, and the investigation should be approved by the quality unit(s).

9.32

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.

9.33

Obsolete and out-dated labels should be destroyed.

9.34

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.

9.35

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.

9.36

A printed label representative of those used should be included in the batch production record.

9.40

There should be documented procedures designed to ensure that correct packaging materials and labels are used.

9.41

Labelling operations should be designed to prevent mix-ups. There should be physical or spatial separation from operations involving other intermediates or APIs.

9.42

Labels used on containers of intermediates or APIs should indicate the name or identifying code, the batch number of the product, and storage conditions, when such information is critical to assure the quality of intermediate or API.

9.43

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, and 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. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or Certificate of Analysis.

9.44

Packaging and labelling 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.

9.45

Packaged and labelled 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.

9.46

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.

10.10

Facilities should be available for the storage of all materials under appropriate conditions (e.g. controlled temperature and humidity when necessary). Records should be maintained of these conditions if they are critical for the maintenance of material characteristics.

10.11

Unless there is an alternative system to prevent the unintentional or unauthorised 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 taken.

10.20

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.

10.21

APIs and intermediates should be transported in a manner that does not adversely affect their quality.

10.22

Special transport or storage conditions for an API or intermediate should be stated on the label.

10.23

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.

10.24

A system should be in place by which the distribution of each batch of intermediate and/or API can be readily determined to permit its recall.

11.10

The independent quality unit(s) should have at its disposal adequate laboratory facilities.

11.11

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 6.6.

11.12

All specifications, sampling plans, and test procedures should be scientifically sound and appropriate to ensure that raw materials, intermediates, APIs, and labels and packaging materials conform to established standards of quality and/or purity. Specifications and test procedures should be consistent with those included in the registration/filing. There can be specifications in addition to those in the registration/filing. 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).

11.13

Appropriate specifications should be established for APIs in accordance with accepted standards and consistent with the manufacturing process. The specifications should include a control of the impurities (e.g. organic impurities, inorganic impurities, and residual solvents). 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.

11.14

Laboratory controls should be followed and documented at the time of performance. Any departures from the above described procedures should be documented and explained.

11.15

Any out-of-specification result obtained should be investigated and documented according to a procedure. This procedure should require analysis of the data, assessment of whether a significant problem exists, allocation of the tasks for corrective actions, and conclusions. Any resampling and/or retesting after OOS results should be performed according to a documented procedure.

11.16

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

11.17

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 recognised source are normally used without testing if stored under conditions consistent with the supplier’s recommendations.

11.18

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.

11.19

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.

11.20

For each batch of intermediate and API, appropriate laboratory tests should be conducted to determine conformance to specifications.

11.21

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.g. retention time), the range of each impurity observed, and classification of each identified impurity (e.g. inorganic, organic, solvent). 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 Guideline Q6B.

11.22

The impurity profile should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data in order to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.

11.23

Appropriate microbiological tests should be conducted on each batch of intermediate and API where microbial quality is specified.

11.40

Authentic Certificates of Analysis should be issued for each batch of intermediate or API on request.

11.41

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. For intermediates or APIs with a retest date, the retest date should be indicated on the label and/or Certificate of Analysis.

11.42

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).

11.43

Certificates should be dated and signed by authorised personnel of the quality unit(s) and should show the name, address and telephone number of the original manufacturer. Where the analysis has been carried out by a repacker or reprocessor, the Certificate of Analysis should show the name, address and telephone number of the repacker/reprocessor and a reference to the name of the original manufacturer.

11.44

If new Certificates are issued by or on behalf of repackers/reprocessors, agents or brokers, these Certificates should show the name, address and telephone number of the laboratory that performed the analysis. 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.

11.50

A documented, on-going testing program should be designed to monitor the stability characteristics of APIs, and the results should be used to confirm appropriate storage conditions and retest or expiry dates.

11.51

The test procedures used in stability testing should be validated and be stability indicating.

11.52

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 smaller-scale drums of similar or identical material composition to the market drums.

11.53

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 two years, fewer than three batches can be used.

11.54

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.

11.55

For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first three months, and at three month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g. 9 month testing) can be considered.

11.56

Where appropriate, the stability storage conditions should be consistent with the ICH guidelines on stability.

11.60

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.g. published data, test results).

11.61

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.

11.62

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.

11.63

A representative sample should be taken for the purpose of performing a retest.

11.70

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.

11.71

Appropriately identified reserve samples of each API batch should be retained for one year after the expiry date of the batch assigned by the manufacturer, or for three years after distribution of the batch, whichever is the longer. For APIs with retest dates, similar reserve samples should be retained for three years after the batch is completely distributed by the manufacturer.

11.72

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.

12.10

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.

12.11

The critical parameters/attributes should normally be identified during the development stage or from historical data, and the ranges necessary for the reproducible operation should be defined. This should include:

12.12

Validation should extend to those operations determined to be critical to the quality and purity of the API.

12.20

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.

12.21

The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted (e.g. retrospective, prospective, concurrent) and the number of process runs.

12.22

A validation report that cross-references the validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the appropriate conclusions, including recommending changes to correct deficiencies.

12.23

Any variations from the validation protocol should be documented with appropriate justification.

12.30

Before starting 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:

12.40

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.

12.41

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

12.42

Prospective validation should normally be performed for all API processes as defined in 12.12. Prospective validation performed on an API process should be completed before the commercial distribution of the final drug product manufactured from that API.

12.43

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.

12.44

An exception can be made for retrospective validation for 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:

(1) Critical quality attributes and critical process parameters have been identified;
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(2) Appropriate in-process acceptance criteria and controls have been established;
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(3) There have not been significant process/product failures attributable to causes other than operator error or equipment failures unrelated to equipment suitability; and
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(4) Impurity profiles have been established for the existing API.

12.45

Batches selected for retrospective validation should be representative of all batches made 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.

12.50

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.g., complex API processes or API processes with prolonged completion times). For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.

12.51

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.

12.52

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.

12.60

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.

12.70

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.

12.71

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.

12.72

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 labelled.

12.73

Sampling should include swabbing, rinsing, or alternative methods (e.g., direct extraction), as appropriate, to detect both insoluble and soluble residues. The sampling methods used should be capable of quantitatively measuring levels of residues remaining on the equipment surfaces after cleaning. Swab sampling may be impractical when product contact surfaces are not easily accessible due to equipment design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor tanks with small ports or handling toxic materials, and small intricate equipment such as micronizers and microfluidizers).

12.74

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.

12.75

Equipment cleaning/sanitization studies should address microbiological and endotoxin contamination for those processes where there is a need to reduce total microbiological count or endotoxins in the API, or other processes where such contamination could be of concern (e.g.,non-sterile APIs used to manufacture sterile products).

12.76

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. Visual inspection can allow detection of gross contamination concentrated in small areas that could otherwise go undetected by sampling and/or analysis.

12.80

Analytical methods should be validated unless the method employed is included in the relevant pharmacopoeia or other recognised standard reference. The suitability of all testing methods used should nonetheless be verified under actual conditions of use and documented.

12.81

Methods should be validated to include consideration of characteristics included within the ICH guidelines on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.

12.82

Appropriate qualification of analytical equipment should be considered before starting validation of analytical methods.

12.83

Complete records should be maintained of any modification of a validated analytical method. Such records should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method.

13.10

A formal change control system should be established to evaluate all changes that may affect the production and control of the intermediate or API.

13.11

Written procedures should provide for the identification, documentation,
appropriate review, and approval of changes in raw materials, specifications, analytical methods, facilities, support systems, equipment (including computer hardware), processing steps, labelling and packaging materials, and computer software.

13.12

Any proposals for GMP relevant changes should be drafted, reviewed, and approved by the appropriate organisational units, and reviewed and approved by the quality unit(s).

13.13

The potential impact of the proposed change on the quality of the intermediate or API should be evaluated. A classification procedure may help in determining the level of testing, validation, and documentation needed to justify changes to a validated process. Changes can be classified (e.g. as minor or major) depending on the nature and extent of the changes, and the effects these changes may impart on the process. Scientific judgement should determine what additional testing and validation studies are appropriate to justify a change in a validated process.

13.14

When implementing approved changes, measures should be taken to ensure that all documents affected by the changes are revised.

13.15

After the change has been implemented, there should be an evaluation of the first batches produced or tested under the change.

13.16

The potential for critical changes to affect established retest or expiry dates should be evaluated. If necessary, samples of the intermediate or API produced by the modified process can be placed on an accelerated stability program and/or can be added to the stability monitoring program.

13.17

Current dosage form manufacturers should be notified of changes from established production and process control procedures that can impact the quality of the API.

14.10

Intermediates and APIs failing to meet established specifications should be
identified as such and quarantined. These intermediates or APIs can be
reprocessed or reworked as described below. The final disposition of rejected materials should be recorded.

14.20

Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and reprocessing by repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, milling) that are part of the established manufacturing process is generally considered acceptable. However, if such reprocessing is used for a majority of batches, such reprocessing should be included as part of the standard manufacturing process.

14.21

Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process. This is not considered to be reprocessing.

14.22

Introducing unreacted material back into a process and repeating a chemical reaction is considered to be reprocessing unless it is part of the established process. Such reprocessing should be preceded by careful evaluation to ensure that the quality of the intermediate or API is not adversely impacted due to the potential formation of by-products and over-reacted materials.

14.30

Before a decision is taken to rework batches that do not conform to established standards or specifications, an investigation into the reason for non-conformance should be performed.

14.31

Batches that have been reworked should be subjected to appropriate evaluation, testing, stability testing if warranted, and documentation to show that the reworked product is of equivalent quality to that produced by the original process. Concurrent validation is often the appropriate validation approach for rework procedures. This allows a protocol to define the rework procedure, how it will be carried out, and the expected results. If there is only one batch to be reworked, then a report can be written and the batch released once it is found to be acceptable.

14.32

Procedures should provide for comparing the impurity profile of each reworked batch against batches manufactured by the established process. Where routine analytical methods are inadequate to characterize the reworked batch, additional methods should be used.

14.40

Recovery (e.g. from mother liquor or filtrates) of reactants, intermediates, or the API is considered acceptable, provided that approved procedures exist for the recovery and the recovered materials meet specifications suitable for their intended use.

14.41

Solvents can be recovered and reused in the same processes or in different processes, provided that the recovery procedures are controlled and monitored to ensure that solvents meet appropriate standards before reuse or co-mingling with other approved materials.

14.42

Fresh and recovered solvents and reagents can be combined if adequate testing has shown their suitability for all manufacturing processes in which they may be used.

14.43

The use of recovered solvents, mother liquors, and other recovered materials should be adequately documented.

14.50

Returned intermediates or APIs should be identified as such and quarantined.

14.51

If the conditions under which returned intermediates or APIs have been stored or shipped before or during their return or the condition of their containers casts doubt on their quality, the returned intermediates or APIs should be reprocessed, reworked, or destroyed, as appropriate.

14.52

Records of returned intermediates or APIs should be maintained. For each return, documentation should include:

15.10

All quality related complaints, whether received orally or in writing, should be recorded and investigated according to a written procedure.

15.11

Complaint records should include:

15.12

Records of complaints should be retained in order to evaluate trends, product-related frequencies, and severity with a view to taking additional, and if appropriate, immediate corrective action.

15.13

There should be a written procedure that defines the circumstances under which a recall of an intermediate or API should be considered.

15.14

The recall procedure should designate who should be involved in evaluating the information, how a recall should be initiated, who should be informed about the recall, and how the recalled material should be treated.

15.15

In the event of a serious or potentially life-threatening situation, local, national, and/or international authorities should be informed and their advice sought.

16.10

All contract manufacturers (including laboratories) should comply with the GMP defined in this Guide. Special consideration should be given to the prevention of cross-contamination and to maintaining traceability.

16.11

Contract manufacturers (including laboratories) should be evaluated by the contract giver to ensure GMP compliance of the specific operations occurring at the contract sites.

16.12

There should be a written and approved contract or formal agreement between the contract giver and the contract acceptor that defines in detail the GMP responsibilities, including the quality measures, of each party.

16.13

The contract should permit the contract giver to audit the contract acceptor's facilities for compliance with GMP.

16.14

Where subcontracting is allowed, the contract acceptor should not pass to a third party any of the work entrusted to him under the contract without the contract giver's prior evaluation and approval of the arrangements.

16.15

Manufacturing and laboratory records should be kept at the site where the activity occurs and be readily available.

16.16

Changes in the process, equipment, test methods, specifications, or other
contractual requirements should not be made unless the contract giver is informed and approves the changes.

17.10

This section applies to any party other than the original manufacturer who may trade and/or take possession, repack, relabel, manipulate, distribute or store an API or intermediate.

17.11

All agents, brokers, traders, distributors, repackers, and relabellers should comply with GMP as defined in this Guide.

17.20

Agents, brokers, traders, distributors, repackers, or relabellers should maintain complete traceability of APIs and intermediates that they distribute. Documents that should be retained and available include:

17.30

Agents, brokers, traders, distributors, repackers, or relabellers should establish, document and implement an effective system of managing quality, as specified in Section 2.

17.40

Repackaging, relabelling and holding of APIs and intermediates should be performed under appropriate GMP controls, as stipulated in this Guide, to avoid mix-ups and loss of API or intermediate identity or purity.

17.41

Repackaging should be conducted under appropriate environmental conditions to avoid contamination and cross-contamination.

17.50

Stability studies to justify assigned expiration or retest dates should be conducted if the API or intermediate is repackaged in a different type of container than that used by the API or intermediate manufacturer.

17.60

Agents, brokers, distributors, repackers, or relabellers should transfer all quality or regulatory information received from an API or intermediate manufacturer to the customer, and from the customer to the API or intermediate manufacturer.

17.61

The agent, broker, trader, distributor, repacker, or relabeller who supplies the API or intermediate to the customer should provide the name of the original API or intermediate manufacturer and the batch number(s) supplied.

17.62

The agent should also provide the identity of the original API or intermediate manufacturer to regulatory authorities upon request. The original manufacturer can respond to the regulatory authority directly or through its authorized agents, depending on the legal relationship between the authorized agents and the original API or intermediate manufacturer. (In this context "authorized" refers to authorized by the manufacturer.)

17.63

The specific guidance for Certificates of Analysis included in Section 11.4 should be met.

17.70

Agents, brokers, traders, distributors, repackers, or relabellers should maintain records of complaints and recalls, as specified in Section 15, for all complaints and recalls that come to their attention.

17.71

If the situation warrants, the agents, brokers, traders, distributors, repackers, or relabellers should review the complaint with the original API or intermediate manufacturer in order to determine whether any further action, either with other customers who may have received this API or intermediate or with the regulatory authority, or both, should be initiated. The investigation into the cause for the complaint or recall should be conducted and documented by the appropriate party.

17.72

Where a complaint is referred to the original API or intermediate manufacturer, the record maintained by the agents, brokers, traders, distributors, repackers, or relabellers should include any response received from the original API or intermediate manufacturer (including date and information provided).

17.80

Returns should be handled as specified in Section 14.52. The agents, brokers, traders, distributors, repackers, or relabellers should maintain documentation of returned APIs and intermediates.

18.10

Section 18 is intended to address specific controls for APIs or intermediates manufactured by cell culture or fermentation using natural or recombinant organisms and that have not been covered adequately in the previous sections. It is not intended to be a stand-alone Section. In general, the GMP principles in the other sections of this document apply. Note that the principles of fermentation for “classical” processes for production of small molecules and for processes using recombinant and non-recombinant organisms for production of proteins and/or polypeptides are the same, although the degree of control will differ. Where practical, this section will address these differences. In general, the degree of control for biotechnological processes used to produce proteins and polypeptides is greater than that for classical fermentation processes.

18.11

The term “biotechnological process” (biotech) refers to the use of cells or organisms that have been generated or modified by recombinant DNA, hybridoma or other technology to produce APIs. The APIs produced by biotechnological processes normally consist of high molecular weight substances, such as proteins and polypeptides, for which specific guidance is given in this Section. Certain APIs of low molecular weight, such as antibiotics, amino acids, vitamins, and carbohydrates, can also be produced by recombinant DNA technology. The level of control for these types of APIs is similar to that employed for classical fermentation.

18.12

The term “classical fermentation” refers to processes that use microorganisms existing in nature and/or modified by conventional methods (e.g. irradiation or chemical mutagenesis) to produce APIs. APIs produced by “classical fermentation” are normally low molecular weight products such as antibiotics, amino acids, vitamins, and carbohydrates.

18.13

Production of APIs or intermediates from cell culture or fermentation involves biological processes such as cultivation of cells or extraction and purification of material from living organisms. Note that there may be additional process steps, such as physicochemical modification, that are part of the manufacturing process. The raw materials used (media, buffer components) may provide the potential for growth of microbiological contaminants. Depending on the source, method of preparation, and the intended use of the API or intermediate, control of bioburden, viral contamination, and/or endotoxins during manufacturing and monitoring of the process at appropriate stages may be necessary.

18.14

Appropriate controls should be established at all stages of manufacturing to assure intermediate and/or API quality. While this Guide starts at the cell culture/fermentation step, prior steps (e.g. cell banking) should be performed under appropriate process controls. This Guide covers cell culture/fermentation from the point at which a vial of the cell bank is retrieved for use in manufacturing.

18.15

Appropriate equipment and environmental controls should be used to minimize the risk of contamination. The acceptance criteria for quality of the environment and the frequency of monitoring should depend on the step in production and the production conditions (open, closed, or contained systems).

18.16

In general, process controls should take into account:

18.17

Where appropriate, the removal of media components, host cell proteins, other process-related impurities, product-related impurities and contaminants should be demonstrated.

18.20

Access to cell banks should be limited to authorized personnel.

18.21

Cell banks should be maintained under storage conditions designed to maintain viability and prevent contamination.

18.22

Records of the use of the vials from the cell banks and storage conditions should be maintained.

18.23

Where appropriate, cell banks should be periodically monitored to determine suitability for use.

18.24

See ICH Guideline Q5D Quality of Biotechnological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products for a more complete discussion of cell banking.

18.30

Where aseptic addition of cell substrates, media, buffers, and gases is needed, closed or contained systems should be used where possible. If the inoculation of the initial vessel or subsequent transfers or additions (media, buffers) are performed in open vessels, there should be controls and procedures in place to minimize the risk of contamination.

18.31

Where the quality of the API can be affected by microbial contamination, manipulations using open vessels should be performed in a biosafety cabinet or similarly controlled environment.

18.32

Personnel should be appropriately gowned and take special precautions handling the cultures.

18.33

Critical operating parameters (for example temperature, pH, agitation rates, addition of gases, pressure) should be monitored to ensure consistency with the established process. Cell growth, viability (for most cell culture processes), and, where appropriate, productivity should also be monitored. Critical parameters will vary from one process to another, and for classical fermentation, certain parameters (cell viability, for example) may not need to be monitored.

18.34

Cell culture equipment should be cleaned and sterilized after use. As appropriate, fermentation equipment should be cleaned, and sanitized or sterilized.

18.35

Culture media should be sterilized before use when appropriate to protect the quality of the API.

18.36

There should be appropriate procedures in place to detect contamination and determine the course of action to be taken. This should include procedures to determine the impact of the contamination on the product and those to decontaminate the equipment and return it to a condition to be used in subsequent batches. Foreign organisms observed during fermentation processes should be identified as appropriate and the effect of their presence on product quality should be assessed, if necessary. The results of such assessments should be taken into consideration in the disposition of the material produced.

18.37

Records of contamination events should be maintained.

18.38

Shared (multi-product) equipment may warrant additional testing after cleaning between product campaigns, as appropriate, to minimize the risk of cross-contamination.

18.40

Harvesting steps, either to remove cells or cellular components or to collect cellular components after disruption, should be performed in equipment and areas designed to minimize the risk of contamination.

18.41

Harvest and purification procedures that remove or inactivate the producing organism, cellular debris and media components (while minimizing degradation, contamination, and loss of quality) should be adequate to ensure that the intermediate or API is recovered with consistent quality.

18.42

All equipment should be properly cleaned and, as appropriate, sanitized after use. Multiple successive batching without cleaning can be used if intermediate or API quality is not compromised.

18.43

If open systems are used, purification should be performed under environmental conditions appropriate for the preservation of product quality.

18.44

Additional controls, such as the use of dedicated chromatography resins or additional testing, may be appropriate if equipment is to be used for multiple products.

18.50

See the ICH Guideline Q5A Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin for more specific information.

18.51

Viral removal and viral inactivation steps are critical processing steps for some processes and should be performed within their validated parameters.

18.52

Appropriate precautions should be taken to prevent potential viral contamination from pre-viral to post-viral removal/inactivation steps. Therefore, open processing should be performed in areas that are separate from other processing activities and have separate air handling units.

18.53

The same equipment is not normally used for different purification steps. However, if the same equipment is to be used, the equipment should be appropriately cleaned and sanitized before reuse. Appropriate precautions should be taken to prevent potential virus carry-over (e.g. through equipment or environment) from previous steps.

19.10

Not all the controls in the previous sections of this Guide are appropriate for the manufacture of a new API for investigational use during its development. Section 19 provides specific guidance unique to these circumstances.

19.11

The controls used in the manufacture of APIs for use in clinical trials should be consistent with the stage of development of the drug product incorporating the API. Process and test procedures should be flexible to provide for changes as knowledge of the process increases and clinical testing of a drug product progresses from pre-clinical stages through clinical stages. Once drug development reaches the stage where the API is produced for use in drug products intended for clinical trials, manufacturers should ensure that APIs are manufactured in suitable facilities using appropriate production and control procedures to ensure the quality of the API.

19.20

Appropriate GMP concepts should be applied in the production of APIs for use in clinical trials with a suitable mechanism of approval of each batch.

19.21

A quality unit(s) independent from production should be established for the approval or rejection of each batch of API for use in clinical trials.

19.22

Some of the testing functions commonly performed by the quality unit(s) can be performed within other organizational units.

19.23

Quality measures should include a system for testing of raw materials, packaging materials, intermediates, and APIs.

19.24

Process and quality problems should be evaluated.

19.25

Labelling for APIs intended for use in clinical trials should be appropriately controlled and should identify the material as being for investigational use.

19.30

During all phases of clinical development, including the use of small-scale facilities or laboratories to manufacture batches of APIs for use in clinical trials, procedures should be in place to ensure that equipment is calibrated, clean and suitable for its intended use.

19.31

Procedures for the use of facilities should ensure that materials are handled in a manner that minimizes the risk of contamination and cross-contamination.

19.40

Raw materials used in production of APIs for use in clinical trials should be evaluated by testing, or received with a supplier’s analysis and subjected to identity testing. When a material is considered hazardous, a supplier's analysis should suffice.

19.41

In some instances, the suitability of a raw material can be determined before use based on acceptability in small-scale reactions (i.e., use testing) rather than on analytical testing alone.

19.50

The production of APIs for use in clinical trials should be documented in laboratory notebooks, batch records, or by other appropriate means. These documents should include information on the use of production materials, equipment, processing, and scientific observations.

19.51

Expected yields can be more variable and less defined than the expected yields used in commercial processes. Investigations into yield variations are not expected.

19.60

Process validation for the production of APIs for use in clinical trials is normally inappropriate, where a single API batch is produced or where process changes during API development make batch replication difficult or inexact. The combination of controls, calibration, and, where appropriate, equipment qualification assures API quality during this development phase.

19.61

Process validation should be conducted in accordance with Section 12 when batches are produced for commercial use, even when such batches are produced on a pilot or small scale.

19.70

Changes are expected during development, as knowledge is gained and the production is scaled up. Every change in the production, specifications, or test procedures should be adequately recorded.

19.80

While analytical methods performed to evaluate a batch of API for clinical trials may not yet be validated, they should be scientifically sound.

19.81

A system for retaining reserve samples of all batches should be in place. This system should ensure that a sufficient quantity of each reserve sample is retained for an appropriate length of time after approval, termination, or discontinuation of an application.

19.82

Expiry and retest dating as defined in Section 11.6 applies to existing APIs used in clinical trials. For new APIs, Section 11.6 does not normally apply in early stages of clinical trials.

19.90

A system should be in place to ensure that information gained during the development and the manufacture of APIs for use in clinical trials is documented and available.

19.91

The development and implementation of the analytical methods used to support the release of a batch of API for use in clinical trials should be appropriately documented.

19.92

A system for retaining production and control records and documents should be used. This system should ensure that records and documents are retained for an appropriate length of time after the approval, termination, or discontinuation of an application.