Pharmaceutical-grade ingredient compliance -
The FDA maintains a database listing approved commercial formulations for human drugs the Orange Book and veterinary drugs the Green Book. For chemicals, a certificate of analysis is usually available upon request.
Skip to main content. I'm Looking for Information About. Nevertheless, the nonclinical safety studies for excipients provides some background:.
Examples of excipients include fillers, extenders, diluents, wetting agents, solvents, emulsifiers, preservatives, flavors, absorption enhancers, sustained release matrices, and coloring agents. EU GMP Basic requirements for active substances used as starting materials - EU GMP for APIs provides GMP guidance for the manufacture of active substances under an appropriate system for managing quality.
FDA expects API manufacturers to apply current Good manufacturing Practice CGMPs to the API process. This Guidance Manual contains specific FDA requirements. APIC - Good manufacturing practices for Active ingredient manufacturers, with EFPIA, APIC - Quality Management System for Active pharmaceutical Ingredient manufacturers - Integrating GMP into ISO , December APIC - Manufacture of sterile active pharmaceutical ingredients - guidance APIC - Guidance on Aspects of Cleaning Validation in Active pharmaceutical Ingredient manufacturing plants - Policy, APIC - Good Manufacturing Practices in Active Pharmaceutical Ingredients Development, APIC - Guidance on aspects of cleaning validation in active pharmaceutical ingredient plants, guidance APIC - Computer validation Guide, December APIC - Guideline for the Establishment of a Control Procedure for Technical Equipment, including related Utilities, Computerised Systems and Facilities used in the Manufacture of APIs and Intermediates revised Nov.
WHO Propasal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms. Eudralex Volume 2C Guidance on elements required to support the significant benefit in comparison with existing therapies of a new therapeutic indication in order to benefit from an extended 11 years marketing protection period November Eudralex Volume 3 NOTE FOR GUIDANCE ON Quality of Biotechnological Products: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin.
Eudralex Volume 3 Reflection paper on the pharmaceutical development of intravenous medicinal products containing active substances solubilised in micellar systems non-polymeric surfactants.
Standardised Letters related to Shared 3rd Party Audits: Letter 2 - Letter to the API Manufacturer. Standardised Letters related to Shared 3rd Party Audits: Letter 3 - Letter from the API Manufacturer to the customer.
APIC - Quality Management System QMS for Active Pharmaceutical Ingredients API Manufacturers - Integrating GMP ICH Q7a into ISO , September FDA Guidance for Industry: Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions Annex Capillary Electrophoresis General Chapter.
Eudralex Volume 3 ICH Q4B Annex Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Capillary Electrophoresis General Chapter. 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.
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: Pharmaceutical-grade ingredient compliance| Comparison of Pharmaceutical Excipients and Food Ingredient Requirements | Most importantly, you can feel confident knowing the ingredients in your drugs are safe from contamination from development to shipping. Bringing over 35 years of textile and flexible packaging experience to Palmetto, Mr. He is skilled in all aspects of manufacturing and engineering of flexible, woven polypropylene plastics. In his free time Mr. King enjoys playing disc golf with his two sons and enjoying the outdoors. When you hire us for your packaging needs, you know you're getting highly qualified professionals who have the expertise and experience to make sure your job is done right. Contact Us. With over 25 years of experience in FIBCs and packaging, no matter what your industry, we are THE bulk bag company to provide you with cost-effective solutions. Accessibility Feedback Terms Of Use Privacy Policy. Signup for exclusive updates and industry insights. Skip to main content Skip to primary sidebar Skip to footer. In This Article:. What Does Pharmaceutical Grade Mean? But, what does pharmaceutical grade mean, really? Our Pharmaceutical Grade Definition So, what does it mean to be pharmaceutical grade? What Is a Pharmaceutical Grade Vitamin? And What Is Pharmaceutical Grade Water? Is Pharmaceutical Grade Good? Pharmaceutical Grade Ensures Purity For one, pharmaceutical grade ingredients ensure purity. Pharmaceutical Grade Ensures Consistency The pharmaceutical grade label also guarantees consistency. Pharmaceutical Grade Protects Every Aspect of a Product Finally, pharmaceutical grade labeling applies to every aspect of a product, from its ingredients to its packaging. Is Pharmaceutical Grade the Same As Medical Grade? Food Grade vs. Purity Standards Pharmaceutical grade products follow strict purity standards. Cost Another difference you as a consumer will see between food grade and pharmaceutical grade products is cost. Ensure You Ship and Store Your Pharmaceutical Grades Correctly Pharmaceutical grade ingredients are essential to an effective product. Key Takeaways on Pharma Grade Pharmaceutical grade product manufacturers adhere to strict protocol and use good manufacturing practices to ensure the best product. Share this post: Facebook Pinterest Twitter Linkedin. Sign up today to receive our latest news and more. Call us today and get it done. Footer With over 25 years of experience in FIBCs and packaging, no matter what your industry, we are THE bulk bag company to provide you with cost-effective solutions. This field is for validation purposes and should be left unchanged. This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out. ACCEPT REJECT. Close Privacy Overview This website uses cookies to improve your experience while you navigate through the website. 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It is mandatory to procure user consent prior to running these cookies on your website. Release tests should include analytical and microbiological controls to evaluate overall quality, ensuring the identity, purity, and functional suitability of the material. Control of specified impurities is a key consideration. These internal tests are performed for release of the material but do not represent a regulatory commitment. This leads to the final question to be considered. Registration: what do you file? What is listed in the registration does not have to match what is sourced or even tested. This returns to the potential disconnect that was presented earlier in Figure 1. At a practical level, how the material is used determines which section of the Common Technical Document CTD will contain the information about the material that is provided to regulatory agencies. What is listed in the registration becomes a regulatory commitment. Based on how the material is used, does the company need to commit to compendial testing in the registration per the applicable monograph? It is recommended that compliance with only one pharmacopoeia be listed in any product registration, according to which particular pharmacopoeia is applicable for the specific country to meet regulatory expectations in the filing. This idea will be further detailed in the following strategy section. Are there additional tests, such as quality attributes and functionality testing, that are critical to product manufacture and should be included in the registration? In determining what to list in the product registration, a company must choose wisely because the decision essentially locks you in. Imagine further that the company wishes to control the particle size of this material, not as a CQA, but to aid in processability during manufacture of the active ingredient. In this example, because it is an important component in the manufacturing process, visibility is needed for the supply chain and change control of the raw material. It must be stressed that procuring compendial grade material does not mean that compendial compliance must be listed in the registration; nor would particle size testing necessarily need to be included. The particle size might be an additional internal test for control, while the company gains more experience with the manufacturing process. If, however, there are disconnects between the different functional groups in the company and in their decisions, it is conceivable that the registration might list compendial compliance based on the material procured and the particle size test based on the testing performed because a consistent approach was not followed. The result is an unnecessary regulatory commitment with which the company must now comply. Any changes to address these challenges will require that the company make updates to the product registrations, with the associated difficulties typical of the change control process. This situation illustrates the intersection of the four questions considered and enables discussion of principles and strategies that can help avoid the potential challenges. The goal is for a company to establish a consistent, cross-functional approach for the selection, sourcing, testing, and filing of materials used to manufacture drug substances and products, in compliance with applicable compendial and regulatory requirements. Consistent principles and strategies should be established that will be followed throughout the product lifecycle by all functional areas in the company. Using the definitions provided earlier, the following principles are proposed:. As stressed before, in establishing the principles within a company, it is important to have the discussion with colleagues from all functional areas involved throughout the drug product lifecycle to develop a consistent approach for the appropriate selection, sourcing, testing, and filing for the materials used. The principles given above enable a company to establish their strategy based on the fundamental use of the material as an excipient or raw material. Figure 3 shows an appropriate strategy for the case where the selection process determines an ingredient will be used as an excipient. The other functional area decisions for sourcing, testing, and filing are shown in the three columns, with the corresponding choices for material grade shown in the colored boxes. Assuming there is an applicable monograph in one or more pharmacopoeia, the sourcing decision for an excipient is either compendial or multi-compendial. The testing decision is also compendial or multi-compendial. The filing decision is compendial, with the recommendation that only one pharmacopoeia is referenced for the material in any registration. The decisions in this strategy can be better understood by looking more closely at specific situations. It is instructive to look at the interplay of the decisions for sourcing and testing when considering whether compendial or multi-compendial grade is the better choice for an excipient used in a particular drug product. It will cost more for a company to purchase an excipient sold as multi-compendial grade because the supplier of the material must perform additional testing to ensure compliance with more than one monograph. This can be done provided the user of the excipient performs at least one specific test to verify the identity of the material. Alternatively, the excipient user can perform all testing needed to ensure multi-compendial compliance for the material. This can be accomplished even if the material is purchased to comply with the monograph in only a single pharmacopoeia. To be considered compendial grade, a material must be prepared according to recognized principles of good manufacturing practice GMP and meet the requirements in the pharmacopoeia monograph, as noted in the USP General Notices 5. monograph requirements. This material can be further tested by the user of the material according to the USP monograph. If the material meets the additional USP requirements, it can be considered to be multi-compendial, because it has been prepared under appropriate GMPs and complies with the monograph requirements in both Ph. and USP. With this approach, there is a potential business risk that must be understood by the quality and procurement functions in the company. The excipient user may be unable to return material to the supplier if they obtain a failing result for an additional test in the USP , when the supplier has not indicated that the material complies with the USP monograph requirements. Alternatively, there is no need to reject the material if it fails USP testing, but the company would need to control the material inventory, so it is not used where USP compliance is required. The most conservative approach is to perform full testing according to the specific tests, methods, and acceptance criteria contained in each monograph. Full multi-compendial testing demands significant resources and time, and, accordingly, will not be the preferred approach in many instances, particularly once the product has reached the supply stage of the lifecycle. There are earlier times during the product lifecycle, however, where this might be a good approach to take. For an excipient used in a drug product biobatch or formal stability batch, demonstration that the material has been tested to comply with applicable pharmacopoeia monographs for the United States, Europe, Japan, and China markets, for example, enables this information to be communicated to regulatory agencies in these countries and may avoid delays in product approval. Obviously, testing would not be required for a national pharmacopoeia if there is no intention to file in that particular country. A company may be able to leverage the outcome of excipient harmonization completed by the Pharmacopoeial Discussion Group PDG to perform testing per one monograph in the USP, Ph. This concept was presented in a different context in the previous article for a drug substance 1 , where a company demonstrates equivalency between their currently approved method and a different method published in a new monograph. This determination of method equivalency between the different monographs enables a company to perform testing per one pharmacopoeia to ensure compliance with the others used in the equivalency studies. The use of a method other than the one in Ph. requires prior approval from regulatory agencies in Europe In the case of internal harmonization of excipients, it is recommended that the Ph. test method be performed to ensure multi-compendial compliance while avoiding this regulatory burden. Turning to the strategy for the regulatory decision, it is important to keep in mind that a company must comply with pharmacopoeia requirements to which they have committed in their product registrations. To ensure global acceptance for compendial grade excipients used in a drug product, a company should demonstrate compliance with USP and Ph. monograph requirements, at a minimum. These global pharmacopoeias are accepted by many regulatory agencies well beyond the geographical boundaries covered by the pharmacopoeia A few additional points are necessary. If the product will be marketed in Japan and there is a JP monograph for the excipient, then compliance with the JP is required for Japan. Filing USP or Ph. in this case would not be accepted by the Japanese health authority. A similar situation is now clear for China. If there is monograph for the excipient in the Chinese Pharmacopoeia ChP , then compliance with the ChP is mandatory for the excipient used in product going to China. The situation for other countries with their own national pharmacopoeia should also be considered, although the broad acceptance of USP and Ph. standards may be suitable to regulators in these countries. Looking more closely at multi-compendial compliance with USP and Ph. monographs for excipients, what should the company actually file in their product registration? This question relates to the pharmacopoeia reference listed for excipients in CTD section 3. While the meaning of this regulatory commitment may be apparent for the US and European countries, it is not as clear to regulators in many other countries around the world. Nor is the meaning necessarily clear to the quality group in a company that needs to test an excipient for use in a product intended for one of these countries. Recall that for Japan and China, compliance with the JP and ChP , respectively, is required if they contain a monograph for the excipient. This means listing USP compliance for excipients in one registration, which may be filed in 75 or more countries that accept USP compliance. Another registration would list Ph. compliance for excipients, to be filed in another 75 or more countries, including all of Europe. The benefit of this approach becomes clear when considering the potential impact on global product registrations resulting from an update to the pharmacopoeia monograph. Executing the change control process to implement the monograph update typically requires some degree of regulatory impact assessment by the chemistry, manufacturing, and controls CMC function of a company to determine if any actions are necessary. Assume, for example, the update is to the USP monograph. By contrast, if the company has filed specific compliance to USP in 75 countries, then the impact assessment is only needed for the registrations in these 75 countries. No change control or impact assessment is needed for the other 75 countries where Ph. compliance has been filed. This approach reduces by half the number of regulatory impact assessments needed by a company as a result of compendial updates. This workload reduction is significant given the time and complexity of looking at so many individual product registrations. Adding the country-specific registration needed for Japan that lists JP excipient compliance and for China that lists ChP excipient compliance, there are a total of only four different registrations needed for global use, acceptable in essentially every country in the world. There are other approaches that may be taken to ensure appropriate compliance for excipients with monographs in the pharmacopoeia. In Europe, the excipient supplier can apply for Certification of Suitability to the Monographs of the European Pharmacopoeia CEP. The CEP procedure has been in place for more than 25 years to provide assessment of the manufacturing and quality controls used for an excipient There are some instances where there is no monograph in the pharmacopoeia for an excipient that will be used in a drug product. Because compendial grade is not an option, the sourcing decision defaults to supply grade to ensure visibility to the supply chain and change control for the excipient. The questions now center on the appropriate testing and filing for the material. Looking first at testing, how does the excipient user establish appropriate specifications when there is no compendial monograph for the material? Should the same methods be used, if they are available from the supplier? Are there tests or methods in the general chapters of the pharmacopoeia that could be used for the material? Should the company apply the same acceptance criteria to the material, or is there a particular range for a quality attribute that is needed for their manufacturing process? Are there other functional requirements that should be added to ensure appropriate control for the excipient? Because the excipient supplier will likely have no visibility to the specific use of the excipient in the drug product, the user must ensure agreement with the supplier on any additional tests or limits for the material. The ultimate goal, as emphasized previously, is to establish overall testing requirements that ensure the excipient has appropriate quality, is fit for purpose in the drug product, and can be procured on an ongoing basis. Once the specifications have been established for the non-compendial excipient, consideration turns to the product registration. In this case, there is not the ability to make the simple but specific reference to quality requirements listed in a monograph for the material. Which of the tests established for the non-compendial excipient should be included in the filing? Clearly, there are tests that are required for the excipient that should be listed, becoming regulatory commitments to control the quality of the material. There may also be some tests that can be maintained as internal tests, as described earlier. Additional information, beyond quality requirements, will also be needed in the registration for a novel excipient. A new product under development included an excipient that had not been previously used by the company. On searching, the CMC group found there were no monographs for the material in either the USP or Ph. The CMC scientist wanted to take the simple and seemingly appropriate action of filing the excipient to comply with the Ph. In discussion with the compendial affairs group, however, it was pointed out that the Ph. This raised the risk that any future change to the Ph. Should the material be filed with the Ph. reference, which would likely be acceptable throughout Europe, but perhaps not as widely accepted by other countries? Is there another approach that could be taken? The compendial affairs group recommended the material be filed as a non-compendial excipient to avoid the compliance risk. However, the specifications listed in the Ph. If questioned upon review by a health authority, the alignment with the Ph. monograph could be shown. It is conceivable that another company would have made a different decision and filed the excipient to meet the Ph. This points to the reality that, taking all considerations into account, there is not always a single decision that is best for all companies. The lesson is that the affected groups should come together and discuss the functional requirements, quality requirements, and regulatory expectations for the material to determine the appropriate strategy. The strategies and functional area decisions for the case where the selection process determines an ingredient will be used as a raw material for the preparation of the drug substance are presented in Figure 4. As shown in the columns, the recommended sourcing decision is supply grade or compendial grade, either of which can provide the desired supply chain and change control visibility for the material. Sourcing compendial grade for the raw material does not mean it would be tested or filed as compendial grade. It is unnecessary to consider multi-compendial grade material as this will simply be more costly to purchase. If compendial or supply grade material is not available, or if it is otherwise suitable for the material to be purchased as a commodity, then reagent-grade material can be considered, with the cautions mentioned earlier taken into account. The testing decision is to include only the minimum requirements that are needed to ensure the raw material is fit for purpose, in terms of its quality and functional attributes. The filing decision is also to include only the minimum requirements necessary, with no reference made to a compendial monograph, if one is available for the material. In establishing the specifications for the material, some tests from an available monograph or from general chapters in the pharmacopoeia might be included, since these can be useful. There should be no commitment to comply with the monograph, however, because that is neither necessary nor appropriate for the intended use of the raw material in drug substance manufacture. Recall the product lifecycle can span many years from development to registration to supply, with many functional areas involved in decision-making throughout the process. Committing to more than is necessary for the raw material in the product registration has unfortunate practical and long-lasting impact to other functional groups in the company. As noted in Figure 4 , the strategy for a residual material would generally align with the raw material strategy. Similar to raw materials, the decisions made for residual materials pose a risk of disconnects between what is filed and what is sourced or tested. Consistent application of the principles and strategies described in this article can help avoid these disconnects, ensure appropriate testing, and reduce the potential compliance burden and risk. Principles and strategies have been provided to help companies develop a consistent, cross-functional approach for the appropriate selection, sourcing, testing, and filing of raw materials used in the preparation of drug substances and excipients used in drug products. Having a common understanding of definitions based on how the materials are used and for material grades based on what is purchased and how it is tested can facilitate appropriate decisions by impacted groups across the product lifecycle. The decision of what is included in the product registration is particularly critical. The often-complex answers to seemingly simple questions-What do you need? What do you buy? What do you test? What do you file? The authors gratefully acknowledge the contribution of Susan J. |
| Main navigation | Phafmaceutical-grade Pharmaceutical-grade ingredient compliance Manufacture of sterile active pharmaceutical Pre-workout fueling ingtedient Pre-workout fueling These complaince and regulations are impacted by material origin and harvesting for excipients and food ingredients. Blending processes should be Increase mental energy controlled and documented, and the blended batch should be tested for conformance to established specifications, where appropriate. Connect with us. 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. Normally, the first three commercial production batches should be placed on the stability monitoring program to confirm the retest or expiry date. |
| GMP Regulations and Compliance for API and Excipients | Prequalification of an API is made with specific reference to the manufacturing details and quality controls described in the APIMF submitted for assessment. A prequalified API is therefore clearly identifiable with a specific APIMF version. An APIMF version may be altered during prequalification assessment, or as a result of post-prequalification changes. Therefore, the version number of the current APIMF is included on the WHO List of Prequalified Active Pharmaceutical Ingredients, to serve as a reference for the production and quality control of that API. As well having their prequalified API s included in the WHO List of Prequalified Active Pharmaceutical Ingredients, successful applicants receive a WHO Confirmation of Active Pharmaceutical Ingredient Prequalification for each API for which they attain prequalification. This contains information regarding the accepted active ingredient specifications, and the assay and related substances test methods. It may be provided by the applicant to interested parties. All applicants must submit a site master file SMF for each manufacturing site of each API and intermediate involved in the preparation of the API for which prequalification is sought. If only part of the API production is carried out at a site — such as analysis or packaging — the SMF need describe only that operation. Each API or intermediate manufacturing site must comply with WHO GMP. Type -Forms -Guidelines -SOPs -Policies -Informational. Topic Anesthesia and Analgesia Enrichment Euthanasia Health and Safety Husbandry Quarantine and Conditioning Records Surgery Veterinary. Related Terms:. edu ACUO is a unit of the U-M Office of the Vice President for Research:. Because ingredients used in any of these markets could be derived from raw materials of natural origin, additional restrictions to prevent exploitation of endangered species 12,13 need to be considered. There are also more specialized requirements to address illegal logging 14 intended to protect vulnerable environments In addition to controls on flora- and fauna-derived materials, conflict mineral concerns require supply chain control on some inorganic materials 16, These conventions and regulations are impacted by material origin and harvesting for excipients and food ingredients. Consumers also may want food ingredients to have attributes that are not defined by safety or quality. The United States Department of Agriculture USDA regulates organic claims, labeling, and practices Furthermore, USDA defines the requirements on labeling bioengineered foods: food containing bioengineered genetic material, which consumers commonly associate with GMO Consumer demands for natural, organic, and GMO bioengineered food are less likely for dietary supplements and currently are very limited for excipients. Although sustainable and fair-trade supply chain verification may be very important for foods, similar concerns for dietary supplements or pharmaceuticals are less likely. Some consumers desire vegan or vegetarian ingredients, and certain regions such as India 21 require vegetarian labeling on food products. These same consumers typically do not hold pharmaceuticals to the same requirement. Religious requirements for food are very clear to the extent that in some countries these requirements are written into law. Kosher and halal are the most common religious requirements, and recognized religious agencies provide detailed requirements on meeting these standards. As such, although halal or kosher ingredients may be desirable for pharmaceutical excipients, acceptance by patients is not a strict requirement, particularly when there is no suitable halal or kosher alternative. There may be other religious dietary requirements, and the degree to which they ascribe those to dietary supplements or drug products may vary. No single quality management system or certification scheme satisfies ingredient requirements for the three markets. Therefore, manufacturers who supply into two or more of these markets need to understand and implement quality management system requirements to meet each of the markets they serve. IFAC, Quality Systems, Food Safety and Good Manufacturing Practices Guide for Food Additives and GRAS Substances , Revision 1 IPEC, Significant Change Guide for Pharmaceutical Excipients , ICH, Q3D, Guideline for Elemental Impurities , Step 4 version December ICH, Q3A, Impurities in New Drug Substances R2 , Step 4 version October US GPO, Dodd Frank Wall Street Reform and Consumer Protection Act of , Section , Conflict Minerals July 10, Luke Grocholl is regulatory affairs expert—pharma food materials, MilliporeSigma; Priscilla Zawislak is global regulatory affairs advocacy manager, DuPont; R. Christian Moreton is principal, FinnBrit Consulting; and Katherine L. Ulman is principal, KLU Consulting. When referring to this article, please cite it as L. Grocholl, et. CONTINUE TO SITE OR WAIT null SECS. About Us Advertise Contact Us Editorial Info Editorial Contacts Editorial Advisory Board Do Not Sell My Personal Information Privacy Policy Terms and Conditions. Comparison of Pharmaceutical Excipients and Food Ingredient Requirements. Published on: April 2, Christian Moreton , Priscilla Zawislak , Katherine L. Ulman , Luke Grocholl. Pharmaceutical Technology , Pharmaceutical Technology, Volume 44, Issue 4. org EXCiPACT Certification Standards for Pharmaceutical Excipient Suppliers: Good Manufacturing Practices, Good Distribution Practices excipact. org Joint International Pharmaceutical Excipient Council—Pharmaceutical Quality Group Good Manufacturing Practices Guide for Pharmaceutical Excipients ipec. |
| Regulatory and Quality Services | 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. The validation protocol should specify critical process steps and acceptance criteria as well as the type of validation to be conducted e. Using the definitions provided earlier, the following principles are proposed: Principles for excipients An excipient should be compendial grade, unless a monograph for that material is not available in the pharmacopoeia. Without a line-of-sight or end-to-end perspective across the product lifecycle, different areas will likely have different understanding and definitions for the materials used during development, continuing into product launch and supply. There should be physical or spatial separation from operations involving other intermediates or APIs. |
| Pharmaceutical vs. Cosmetic Grade Products Detroit | Pre-workout fueling, they simply Pharmaceytical-grade to be generally ingreduent as safe for Pre-workout fueling cpmpliance consume. Any Pre-workout fueling from compliande practice should be evaluated to Pharmceutical-grade that there are Pre-workout fueling detrimental Mushroom Risotto Recipe on the material's ingredint Pre-workout fueling use. Packaging Pharmaceutical-grade ingredient compliance Any Memory retention strategies intended to Pharmaceutical-ggade an intermediate or API during storage and cokpliance. Buildings used in the manufacture of intermediates and APIs should be properly maintained and repaired and kept in a clean condition. If, however, there are disconnects between the different functional groups in the company and in their decisions, it is conceivable that the registration might list compendial compliance based on the material procured and the particle size test based on the testing performed because a consistent approach was not followed. 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. |
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How are the active ingredients of your medicine made? Let's talk about the discovery of APIsPharmaceutical-grade ingredient compliance -
If only part of the API production is carried out at a site — such as analysis or packaging — the SMF need describe only that operation. Each API or intermediate manufacturing site must comply with WHO GMP.
Manufacturers who submit an application for prequalification should therefore request inspection by WHO of the relevant manufacturing site s so that compliance with WHO GMP can be assessed. Procedure for assessing the acceptability, in principle, of active pharmaceutical ingredients for use in pharmaceutical products WHO Technical Report Series, No.
Clarification on the process for introducing a supplier of non-plant-derived artemisinin 1 November FAQ: Active pharmaceutical ingredient API micronization 13 September FAQ: Active pharmaceutical ingredient master files APIMFs 15 April Use of ICHQ3D guideline in the assessment of APIMFs submitted in support of an FPP or prequalified API 18 October Active Pharmaceutical Ingredients.
Active Pharmaceutical Ingredients Prequalification of active pharmaceutical ingredients APIs is an independent procedure that identifies APIs that are of good quality and manufactered in compliance with WHO Good Manufacturing Practices GMP.
Routes to API prequalification There are three possible routes to API prequalification. Full assessment of an APIMF not previously assessed by WHO. Abridged assessment of an APIMF previously assessed by WHO in support of an application for FPP prequalification.
Abridged assessment of an APIMF accepted previously by an authority applying stringent standards. Manufacturing site requirements All applicants must submit a site master file SMF for each manufacturing site of each API and intermediate involved in the preparation of the API for which prequalification is sought.
Are there residual solvents or elemental impurities present? Depending on its use, is there a need to consider microbiological quality or sterility?
The functional and quality requirements for the materials determined during development are important to other groups involved later in the product lifecycle.
These requirements will be tested by the quality groups to ensure the identity, purity, and performance of the materials. The requirements may eventually be listed and justified in product registrations, with potential impact on post-approval change control. At a certain point, questions arise as to the availability of the material.
These sourcing considerations are not necessarily fundamental during early development but are critical in late development and commercialization. Sourcing: what do you buy?
Again, you start with the question of how it is used because that, in many ways, determines what you buy. The development scientist may pull a raw material or excipient off the laboratory shelf to start their work.
The material may have been purchased through a chemical catalog or it could be a promotional sample from a potential supplier. The scientist might check what is available in the chemical stock or manufacturing area that can be used in development studies.
There is still a need to understand the critical quality attributes CQAs for the material to enable discussion with potential suppliers. At this stage, there is a focus on what is available. Is there only one supplier or are there multiple sources that can provide the material?
Is visibility to the supply chain or change control necessary and possible for the material? As product development proceeds, considerations of the cost and available quantities become important.
If there are multiple sources for the material, what is the basis for choosing one supplier over others? Is there a need to qualify more than one supplier in case of material shortages? What experiments are needed to ensure suitability of materials from different suppliers for use in the specific formulation?
Have the suppliers been previously audited by the company? Were the audit findings acceptable? Are specific materials with different characteristics available e. All of these questions lead to the ultimate determination of the materials and suppliers that will be used in the manufacture of the drug substance and product.
These decisions also impact the testing performed and provide information about what may be filed in product registrations.
Typically, the purchased materials should be compendial, multi-compendial, or supply grade. Quality: what do you test? If the material is used as an excipient and there are applicable monographs, the quality groups need to ask whether they will perform all tests in one or more pharmacopoeias.
In which countries will the product be filed? This determines which pharmacopoeias may be applicable when ensuring compendial or multi-compendial compliance. What if the material is used as an excipient but is non-compendial, meaning there is no monograph for the material in the pharmacopoeia?
Understanding CQAs for the intended use is again important so that quality testing can be performed to control these characteristics in releasing the material. What tests are performed by the supplier?
One key point in going through the exercise at this stage is that there must be discussion and agreement with the supplier for any additional tests or different limits that will be required based on the use of the material. A company making these decisions in a vacuum or without interaction with the supplier can put the availability of the material at risk and create potential challenges for the company.
Release tests should include analytical and microbiological controls to evaluate overall quality, ensuring the identity, purity, and functional suitability of the material. Control of specified impurities is a key consideration. These internal tests are performed for release of the material but do not represent a regulatory commitment.
This leads to the final question to be considered. Registration: what do you file? What is listed in the registration does not have to match what is sourced or even tested.
This returns to the potential disconnect that was presented earlier in Figure 1. At a practical level, how the material is used determines which section of the Common Technical Document CTD will contain the information about the material that is provided to regulatory agencies.
What is listed in the registration becomes a regulatory commitment. Based on how the material is used, does the company need to commit to compendial testing in the registration per the applicable monograph?
It is recommended that compliance with only one pharmacopoeia be listed in any product registration, according to which particular pharmacopoeia is applicable for the specific country to meet regulatory expectations in the filing.
This idea will be further detailed in the following strategy section. Are there additional tests, such as quality attributes and functionality testing, that are critical to product manufacture and should be included in the registration? In determining what to list in the product registration, a company must choose wisely because the decision essentially locks you in.
Imagine further that the company wishes to control the particle size of this material, not as a CQA, but to aid in processability during manufacture of the active ingredient.
In this example, because it is an important component in the manufacturing process, visibility is needed for the supply chain and change control of the raw material. It must be stressed that procuring compendial grade material does not mean that compendial compliance must be listed in the registration; nor would particle size testing necessarily need to be included.
The particle size might be an additional internal test for control, while the company gains more experience with the manufacturing process. If, however, there are disconnects between the different functional groups in the company and in their decisions, it is conceivable that the registration might list compendial compliance based on the material procured and the particle size test based on the testing performed because a consistent approach was not followed.
The result is an unnecessary regulatory commitment with which the company must now comply. Any changes to address these challenges will require that the company make updates to the product registrations, with the associated difficulties typical of the change control process.
This situation illustrates the intersection of the four questions considered and enables discussion of principles and strategies that can help avoid the potential challenges. The goal is for a company to establish a consistent, cross-functional approach for the selection, sourcing, testing, and filing of materials used to manufacture drug substances and products, in compliance with applicable compendial and regulatory requirements.
Consistent principles and strategies should be established that will be followed throughout the product lifecycle by all functional areas in the company. Using the definitions provided earlier, the following principles are proposed:.
As stressed before, in establishing the principles within a company, it is important to have the discussion with colleagues from all functional areas involved throughout the drug product lifecycle to develop a consistent approach for the appropriate selection, sourcing, testing, and filing for the materials used.
The principles given above enable a company to establish their strategy based on the fundamental use of the material as an excipient or raw material. Figure 3 shows an appropriate strategy for the case where the selection process determines an ingredient will be used as an excipient.
The other functional area decisions for sourcing, testing, and filing are shown in the three columns, with the corresponding choices for material grade shown in the colored boxes. Assuming there is an applicable monograph in one or more pharmacopoeia, the sourcing decision for an excipient is either compendial or multi-compendial.
The testing decision is also compendial or multi-compendial. The filing decision is compendial, with the recommendation that only one pharmacopoeia is referenced for the material in any registration.
The decisions in this strategy can be better understood by looking more closely at specific situations. It is instructive to look at the interplay of the decisions for sourcing and testing when considering whether compendial or multi-compendial grade is the better choice for an excipient used in a particular drug product.
It will cost more for a company to purchase an excipient sold as multi-compendial grade because the supplier of the material must perform additional testing to ensure compliance with more than one monograph. This can be done provided the user of the excipient performs at least one specific test to verify the identity of the material.
Alternatively, the excipient user can perform all testing needed to ensure multi-compendial compliance for the material. This can be accomplished even if the material is purchased to comply with the monograph in only a single pharmacopoeia.
To be considered compendial grade, a material must be prepared according to recognized principles of good manufacturing practice GMP and meet the requirements in the pharmacopoeia monograph, as noted in the USP General Notices 5.
monograph requirements. This material can be further tested by the user of the material according to the USP monograph. If the material meets the additional USP requirements, it can be considered to be multi-compendial, because it has been prepared under appropriate GMPs and complies with the monograph requirements in both Ph.
and USP. With this approach, there is a potential business risk that must be understood by the quality and procurement functions in the company. The excipient user may be unable to return material to the supplier if they obtain a failing result for an additional test in the USP , when the supplier has not indicated that the material complies with the USP monograph requirements.
Alternatively, there is no need to reject the material if it fails USP testing, but the company would need to control the material inventory, so it is not used where USP compliance is required. The most conservative approach is to perform full testing according to the specific tests, methods, and acceptance criteria contained in each monograph.
Full multi-compendial testing demands significant resources and time, and, accordingly, will not be the preferred approach in many instances, particularly once the product has reached the supply stage of the lifecycle.
There are earlier times during the product lifecycle, however, where this might be a good approach to take. For an excipient used in a drug product biobatch or formal stability batch, demonstration that the material has been tested to comply with applicable pharmacopoeia monographs for the United States, Europe, Japan, and China markets, for example, enables this information to be communicated to regulatory agencies in these countries and may avoid delays in product approval.
Obviously, testing would not be required for a national pharmacopoeia if there is no intention to file in that particular country. A company may be able to leverage the outcome of excipient harmonization completed by the Pharmacopoeial Discussion Group PDG to perform testing per one monograph in the USP, Ph.
This concept was presented in a different context in the previous article for a drug substance 1 , where a company demonstrates equivalency between their currently approved method and a different method published in a new monograph.
This determination of method equivalency between the different monographs enables a company to perform testing per one pharmacopoeia to ensure compliance with the others used in the equivalency studies.
The use of a method other than the one in Ph. requires prior approval from regulatory agencies in Europe In the case of internal harmonization of excipients, it is recommended that the Ph.
test method be performed to ensure multi-compendial compliance while avoiding this regulatory burden. Turning to the strategy for the regulatory decision, it is important to keep in mind that a company must comply with pharmacopoeia requirements to which they have committed in their product registrations.
To ensure global acceptance for compendial grade excipients used in a drug product, a company should demonstrate compliance with USP and Ph. monograph requirements, at a minimum.
These global pharmacopoeias are accepted by many regulatory agencies well beyond the geographical boundaries covered by the pharmacopoeia A few additional points are necessary. If the product will be marketed in Japan and there is a JP monograph for the excipient, then compliance with the JP is required for Japan.
Filing USP or Ph. in this case would not be accepted by the Japanese health authority. A similar situation is now clear for China.
If there is monograph for the excipient in the Chinese Pharmacopoeia ChP , then compliance with the ChP is mandatory for the excipient used in product going to China. The situation for other countries with their own national pharmacopoeia should also be considered, although the broad acceptance of USP and Ph.
standards may be suitable to regulators in these countries. Looking more closely at multi-compendial compliance with USP and Ph. monographs for excipients, what should the company actually file in their product registration?
This question relates to the pharmacopoeia reference listed for excipients in CTD section 3. While the meaning of this regulatory commitment may be apparent for the US and European countries, it is not as clear to regulators in many other countries around the world.
Nor is the meaning necessarily clear to the quality group in a company that needs to test an excipient for use in a product intended for one of these countries. Recall that for Japan and China, compliance with the JP and ChP , respectively, is required if they contain a monograph for the excipient.
This means listing USP compliance for excipients in one registration, which may be filed in 75 or more countries that accept USP compliance. Another registration would list Ph.
compliance for excipients, to be filed in another 75 or more countries, including all of Europe. The benefit of this approach becomes clear when considering the potential impact on global product registrations resulting from an update to the pharmacopoeia monograph.
Executing the change control process to implement the monograph update typically requires some degree of regulatory impact assessment by the chemistry, manufacturing, and controls CMC function of a company to determine if any actions are necessary.
Assume, for example, the update is to the USP monograph. By contrast, if the company has filed specific compliance to USP in 75 countries, then the impact assessment is only needed for the registrations in these 75 countries.
No change control or impact assessment is needed for the other 75 countries where Ph. compliance has been filed. This approach reduces by half the number of regulatory impact assessments needed by a company as a result of compendial updates.
This workload reduction is significant given the time and complexity of looking at so many individual product registrations. Adding the country-specific registration needed for Japan that lists JP excipient compliance and for China that lists ChP excipient compliance, there are a total of only four different registrations needed for global use, acceptable in essentially every country in the world.
There are other approaches that may be taken to ensure appropriate compliance for excipients with monographs in the pharmacopoeia. In Europe, the excipient supplier can apply for Certification of Suitability to the Monographs of the European Pharmacopoeia CEP.
The CEP procedure has been in place for more than 25 years to provide assessment of the manufacturing and quality controls used for an excipient There are some instances where there is no monograph in the pharmacopoeia for an excipient that will be used in a drug product.
Because compendial grade is not an option, the sourcing decision defaults to supply grade to ensure visibility to the supply chain and change control for the excipient.
The questions now center on the appropriate testing and filing for the material. Looking first at testing, how does the excipient user establish appropriate specifications when there is no compendial monograph for the material? Should the same methods be used, if they are available from the supplier?
Are there tests or methods in the general chapters of the pharmacopoeia that could be used for the material? Should the company apply the same acceptance criteria to the material, or is there a particular range for a quality attribute that is needed for their manufacturing process?
Are there other functional requirements that should be added to ensure appropriate control for the excipient?
Because the excipient supplier will likely have no visibility to the specific use of the excipient in the drug product, the user must ensure agreement with the supplier on any additional tests or limits for the material.
The ultimate goal, as emphasized previously, is to establish overall testing requirements that ensure the excipient has appropriate quality, is fit for purpose in the drug product, and can be procured on an ongoing basis.
Once the specifications have been established for the non-compendial excipient, consideration turns to the product registration. In this case, there is not the ability to make the simple but specific reference to quality requirements listed in a monograph for the material.
Which of the tests established for the non-compendial excipient should be included in the filing? Clearly, there are tests that are required for the excipient that should be listed, becoming regulatory commitments to control the quality of the material.
There may also be some tests that can be maintained as internal tests, as described earlier. Additional information, beyond quality requirements, will also be needed in the registration for a novel excipient. A new product under development included an excipient that had not been previously used by the company.
On searching, the CMC group found there were no monographs for the material in either the USP or Ph.
A Pharmaceuticaal-grade understanding Pre-race fueling for long-distance runners the Pharmaceutical-grrade Manufacturing Pharmaceutical-grade ingredient compliance for Ingreedient Pharmaceutical Ingredients and ingrediebt Pharmaceutical-grade ingredient compliance important comoliance drug manufactures. As Pharmaceutical-grade ingredient compliance APIs and Excipients are Pre-workout fueling for use by patients, manufacturers, distributors, and the entire supply chain are required to Pharmaceutical-frade certain high standards Pre-workout fueling forth by the regulatory authorities. This article provides some of the related deficiencies found during inspections of manufacturing facilities. These examples will help you avoid common pitfalls with respect to APIs and Excipients. At the end of this article, you will find links to relevant regulatory documents categorized by APIs and Excipients. An active pharmaceutical ingredient is defined in ICH Q7 as "any substance or mixture of substances intended to be used in the manufacture of a drug product and that, when used in the production of a drug, becomes an active ingredient in the drug product.
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