A master plan is an invaluable document for both new and existing programs. This document may be "live" (subject to periodic revision) or static (created at one moment in time). Some firms archive master plans within a quality manual, while others place the information within a standard operating procedure. 2
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System procedures. In order to qualify new RMs from new or existing suppliers, several GMP procedures and systems are needed (see Table 2). In writing these procedures, consider compliance as well as efficiency. Check that the different documents link with each other appropriately and do not contradict each other. Avoid the extremes of lumping many procedures into one document or splitting integrated procedures into different documents. Check that the procedures are clearly written and can be consulted and followed while on the floor.
In contrast, an organization with a mature, marketed product is unlikely to have frequent changes in RMs, and long-term supplier relationships are commonly in place. Any changes may require overcoming regulatory hurdles and are highly undesirable. Consequently, all RMs are likely to be fully qualified before use and the quality program will focus on maintenance and monitoring of the qualified state.
Business needs. In establishing an RM qualification program, first determine your internal business requirements. A development organization will usually need a rapid, flexible RM qualification process that can quickly assess up to 100 or more new materials and suppliers and approve them for at least provisional use. Furthermore, changes in RMs and suppliers are expected during development. 5,6 Therefore, full qualification of an RM may proceed in parallel with its use and should be completed at a defined project milestone.
A firm faces the practical challenge of establishing and operating an efficient, compliant system that assures continuous supply of quality RMs that are sampled, tested, and then released for manufacturing needs on time. A properly sized and managed warehouse provides a buffer zone where unpredictable RM problems (back orders, late deliveries, and items failing to meet specifications) can be resolved without delaying manufacturing. However, it is undesirable to build large warehouses and store huge inventories if materials must be discarded because they expire before use. Therefore, it is important for supply chain management to reduce the probability of receiving RMs that fail to meet specifications. This is part of the payoff of a robust and sustainable vendor and RM qualification program.
Table 1 summarizes the applicable regulations for pharmaceutical products of various types, and summarizes some of the differences between US and European regulations. These differences may create complex challenges for the firm that manufactures multiple profile classes of products for worldwide sale. Considering the rapid rate of change to these regulations, sustaining a compliant, effective program requires a strategic approach.
RM qualification should be carefully defined in GMP procedures and placed under strict change control. Both the chemical entity and suppliers must be qualified, usually in tandem. RMs deemed "critical" require testing of more supplier lots for more attributes and extensive supplier evaluation before qualification is achieved. The critical status of an RM is related directly to its intended use in the process and to the potential risk created by a quality deficit in the RM that may adversely impact the product's identity, purity, potency, toxicity, or efficacy. 11,12 An RM may be critical to one process but not to another. Each firm must identify which materials are critical and justify the choices made and the additional oversight required.
Regulatory requirements in the pharmaceutical industry have evolved over time to reduce the probability, or risk, of such events. Some of the most important actions a firm takes to reduce risk include setting specifications that define and control the RMs, testing to verify identity and quality, and establishing systems to prevent the use of unsuitable materials. 3
Legally, a pharmaceutical firm takes on full responsibility for the quality of the RMs it purchases and uses in a cGMP manufacturing process. Consequently, it is in the business interest of a firm to exercise reasonable oversight of suppliers and test laboratories and to characterize RMs appropriately. 9,10
Patient safety is a key reason for this requirement, dating back to several unfortunate events within the pharmaceutical and food industries. In one incident, the use of an unsuitable RM led to widespread toxicity, resulting in hallucinations and other severe symptoms. 8 Mix-ups and errors of identity have also occurred. For example, the accidental use of ethylene glycol instead of propylene glycol resulted in morbidity and mortality.
An RM qualification and control program is considered a key factor in assuring the quality of medicinal drugs, yet it is often deemed of secondary importance at a busy firm. Usually, RM testing is not considered scientifically challenging or exciting - until, of course, the supply chain is imperiled by a single failure. At this point, a great deal of scientific and compliance information must be quickly sifted through and presented to an investigation team, then both short-term and long-term actions initiated. The data are often not readily accessible or transparent and require the collaboration of subject matter experts to integrate and interpret.
Quality assurance for finished pharmaceuticals, biopharmaceuticals, medical devices, and active pharmaceutical ingredients (APIs) includes the specification and control of those components that have product contact during manufacturing, that is, the raw materials (RMs). 1-6
A master plan records basic decisions and assumptions, codifying company philosophies and corporate policies related to quality. Since the document is kept centrally, it can be used to archive organizational history, assumptions, and knowledge. It will be retrievable long after meeting minutes are lost, and can be cited by other documents. The master plan can include references, discussion of any interpretation issues, and the company's formal commitment to quality.
Table 4. Compliance concerns
Table 4. Continued - Compliance concerns
Creating a master plan has a further, indirect benefit. By documenting key assumptions, roles, and responsibilities, cross-functional dialogue occurs and team members can improve their alignment, engage in continuous improvement, and better understand their customers' needs. Inconsistencies in the strategy or gaps in team assignments are exposed and can be addressed before issues arise.7
Table 3 lists typical sections of a master plan. This information also may be captured in other documents, such as quality manuals or system SOPs. Regardless of the document's name, be sure that it is linked to cGMP systems and the information is accurate, archived, and traceable.
Quality concerns. The program also needs to have built-in responses when quality issues are discovered by QC testing or by QA audits. One common disconnect, particularly in firms where QC and QA are each part owners of the RM control system, is that the system does not respond quickly to new information. As described in the ANSI/ASQ standard Z1.4 for sampling, switching rules should be defined to permit increased testing (and other oversight actions such as auditing) when an RM lot fails to meet specifications.13 Switching rules also can define when reduced testing is appropriate - and save the firm money without significantly increasing risks. Similarly, an appropriate response to adverse audit findings may include increased QC testing and an adjustment in the frequency of follow-up audits. To make this happen reliably, the nonconforming materials control system, the audit program, and the RM testing programs must include linkages and notifications. A review of several FDA warning letters and 483s (issued to firms at the end of inspections), suggests that some firms' systems are not sufficiently agile to respond to new RM issues in a timely way, creating compliance risk and negative findings. Table 4 summarizes recent deficiencies that were cited by FDA from to .14-16
Figure 1.
Process thinking is especially helpful in setting up the system for RM and supplier qualification. Often, a specialized team member conducts a single step in the qualification process and then hands off the data to the next team member. Process engineers know that errors and miscommunications occur at interfaces between people and organizations; compliance auditors tend to look for deficiencies at these points.
10
Therefore, creating a committee of key members involved in RM processes facilitates communication, helps ensure that information is not lost or garbled during transfers, and establishes a structure that can handle RM non-conformances.
Figure 1 shows a flow chart for the RM qualification process. The tasks listed are documented in and driven by SOPs or other GMP documents. Depending on the organization, several different work units (such as QC, purchasing, shipping and receiving, manufacturing, and QA) may participate. Both the quality and manufacturing units approve suppliers and RMs. However, in order to maintain objectivity and minimize conflicts of interest, regulations require that the quality unit has oversight and the sole authority to disposition RMs for release or rejection.
The following elements should be part of an RM qualification exercise. Note that some steps may be combined and several are concurrent.
Step 1. Collect information regarding the RM: What grades are available, and what do suppliers test for and set specifications upon? Is the material listed in a compendium such as the US Pharmacopeia, European Pharmacopeia, or Japanese Pharmacopeia? (Compendial materials are well defined and accepted as suitable for finished pharmaceutical use.)17-19 How do the stated specifications compare to actual values reported for a single lot? Is this RM critical or noncritical, based on its intended use? (See Table 5 for examples of critical RMs.)
Table 5. Examples of materials defined as critical
Step 2. Determine the qualification strategy and set your acceptance criteria for this RM. The purpose of qualification is to generate evidence that your firm can rely on the supplier's certificate of analysis and start defining the quality profile of the RM.
The quality profile includes those chemical, biochemical, or microbiological characteristics consistently possessed by the RM and those attributes required by your process. Therefore, it may extend beyond those tests reported on the certificate of analysis. For a critical material, all tests included on the certificate of analysis should be performed.9 Similarly, compendial materials should be tested against the full, current compendium since this is the claim being verified. Use the data to "qualify" the supplier's testing program (that is, show that their results are believable).
Some firms defer qualification activity for noncritical RMs until later in clinical development and accept the low risk that unknown, untested attributes could impact their product.7 Noncritical RMs (for example, lipids added to cell culture media) are often accepted on certificate of analysis plus identity confirmation, after at least one lot has undergone full testing. A "paperwork" review of the actual test values reported on each supplier's certificate against the written specification verifies that each lot received meets the specification. Remember, however, that if you do not perform all testing, it will not be possible to detect some problems. Most regulatory authorities expect that full qualification is completed prior to pivotal clinical trials.5 During periodic review of specifications, such risk-based decisions should be reviewed. This is also the time to decide whether a second source should be, or can be, qualified.
Step 3. Analyze the test results and any information derived from audits or supplier evaluations. Determine the nature of information provided by each test. Some are obvious, such as purity, activity, and identity. Others, such as impurities, moisture, bioburden, or country of origin, may be less directly related to your immediate use of the material, yet still important. Do these tests directly relate to suitability for use, safety to the patient, cross-contamination or mix-up detection, or stability of the material?
Step 4. Based on the data obtained during qualification, approve the final selection of the tests you will perform on each incoming lot for routine release. The data may show that some tests do not provide useful information or that tests not listed on the certificate of analysis are quality-indicating and should be performed routinely. These will be listed on the RM release specification. The test results should be compared with the specifications as well as to the results that were reported by the supplier on the certificate of analysis. Investigate discrepancies between your test results and the suppliers' even if both values are within release specifications.
The regulations require identity confirmation on every receipt of each RM.1-3,6 European regulations differ for excipients and currently require sampling every container for identity. A new WHO draft document - with major cost implications if implemented - suggests that this should also be applied to in-process RMs, although it is likely eclipsed by existing EU and FDA regulations for pharmaceuticals.20 Appearance testing should always be done, since it is an inexpensive and useful way to spot several types of quality problems. Other tests may be added based on the results of your qualification testing, your process and its requirements, and other knowledge that you have. For example, it may be useful to watch for particles or heavy metals if you know that the container or closure used for the RM - or the equipment used for its manufacture - has the potential to shed such materials or if you have seen such a problem in the past.
Step 5. Analyze the data obtained during qualification. Did the RM and the supplier both meet acceptance criteria that were defined in Step 2? If so, document the successful qualification in your cGMP records as a status change, add the RM to the qualified list, and put it into the periodic review program to be overseen by the RM committee. This list should be used to control all ordering of cGMP RMs to ensure that unqualified RMs are not accidentally used. If the data are not satisfactory, consider other actions that can mitigate risk, including vendor follow-ups and testing of other grades, other sources, or both to find suitable materials. Note that it is possible to qualify the RM as suitable for use in the process, while not qualifying the supplier (usually based on audits). Suppliers may be given status labels such as: provisional, qualified, certified, or "avoid using." When the supplier's status is not ideal, a major goal of the committee is to work with the supplier on addressing the concerns, with the long-term goal of upgrading status.10
Step 6. Finalize the frequency of requalification - when you will next put a lot (or lots) of this RM from this supplier through full testing. This lot is called the skip lot. Firms themselves decide the frequency of requalification (no guidance on suitable periods is provided in the regulations). The frequency may be based on calendar dates, set as a skip-lot system (every ten supplier lots, for example), or both. Ensure that your GMP system will notify QC and QA when a skip lot is coming up because the testing will take longer, and the lot's release will be delayed. When the skip lot is approaching, consider that the QC laboratory may be out of practice in performing some tests; a training period may be useful.
Once an RM and its supplier are qualified, it is necessary to maintain that qualification. Suppliers may change their processes, facilities, or equipment. Corporate entities may merge or divest, changing their approaches to and control over quality. Process scale-up often results in changed requirements for RM containers and closures that affect RM quality, stability, and performance as well as sampling methods. Sampling and testing methods change, for example, when a solvent is received in a railroad tank car instead of in a bottle or carboy.
To respond to unexpected issues with RMs, suppliers, or the entire system, ensure that adequate checks and monitoring systems are in place. This area is the most important in keeping a quality operation in running order - and one that is most cited by FDA during inspections.14 Activities undertaken to sustain qualification include audits or other supplier evaluation activities such as trending of test data from the QC lot-testing program and periodic full testing of representative lots of the RM.9,10 Consider if you will be able to detect a new problem in a timely manner and whether the systems require that your team investigates problems with appropriate urgency and depth, finds the root causes, and follows up appropriately. Follow-up must address both any product lots affected by the current situation and whether preventive action is warranted to reduce the probability that the event will recur.
To ensure a sustainable RM qualification program:
Controlling the quality of RMs used during manufacturing by qualifying the materials and their suppliers helps ensure that a firm's final product is well-defined, consistent, and suitable for its intended use. Without qualification, product batches can be lost, production schedules can be delayed, and the supply chain can become unpredictable. Qualification provides documented assurance - enabling a firm to perform risk analysis when it accepts the legal and regulatory responsibilities that go with producing pharmaceutical products.
1. FDA. Current good manufacturing practices for finished pharmaceuticals.
Code of Federal Regulations, Title 21, Part 211.80-94, 211.101, 211.184
as amended 1 Apr .
2. FDA. Quality system regulation. Code of Federal Regulations, Title 21, Part 820 revised 1 Apr .
3. EMEA. Medicinal products for human and veterinary use. GMP Guide (Volume 4) .
4. EMEA. Sampling of starting and packaging materials. GMP Guide (Volume 4) Annex 8 .
If you want to learn more, please visit our website Pharmaceutical Raw Materials suppliers.
5. EMEA. Manufacture of investigational medicinal products. GMP Guide (Volume 4) Annex 13 revised Jul.
6. ICH. Good manufacturing practice for active pharmaceutical ingredients. Q7A. Geneva; .
7. Del Tito BJ, Tremblay M, Shadle P. Qualification of raw materials for clinical biopharmaceutical manufacturing. BioPharm ; 9(10).
8. Thereapeutic Goods Administration. TGA reminds Australians of the potential danger of Pan Pharmaceuticals [press release]. Woden, Australia: TGA; Aug 24.
9. Lubiniecki AS, Shadle PJ. Raw material considerations. Dev. Biol. Standard ; 91:65-72.
10. Dolecek G. Vendor audit and certification programs. Pharmaceutical Engineering ; 17:24.
11. ICH. Specifications: test procedures and acceptance criteria for new drug substances and new drug products - chemical substances. Q6A. Geneva; .
12. ICH. Specifications: test procedures and acceptance criteria for biotechnological/biological products. Q6B. Geneva; .
13. ANSI/ASQC Z1.4-. Sampling procedures and tables for inspection by attributes. Milwaukee (WI): ASQC Quality Press.
14. Recent inspection findings. Excerpted from BioQuality: i2i Corporation. Idyllwild (CA); -.
15. FDA. FDA's electronic freedom of information reading room - warning letters and responses. Available from URL: http://www.fda.gov/foi/warning.htm .
16. ICH. Validation of analytical procedures: methodology. Q2B. Geneva; .
17. USP. The United States pharmacopeia. 27th ed. Rockville (MD): United States Pharmacopeial Convention; .
18. European Pharmacopeia Commission. European pharmacopeia. 5th ed. Strasbourg, France: The Commission; .
19. EMEA. Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products. London; May 31.
20. WHO. Guideline for sampling of pharmaceutical and related materials. Draft . Avaliable from URL: http://www.who.int/medicines/organization/qsm/activities/qualityassurance/gmp/gmptwo.html .
21. CPMP. Note for guidance on viral validation. In: Commissions of the EC, rules governing medicinal products in the EC, Vol 3, Addendum 2. Luxembourg: Office for Official Publications of the EC; .
22. Seely RJ, Wight HD, Fry HH, Rudge, Slaff, GF. and Rudge. Validation of chromatography resin useful life. BioPharm ; 7(7).
There is undoubtedly a need for improved supply chain flexibility to address shortages. In cases where raw materials are single sourced, supplier manufacturing problems or product facility closures could result in manufacturing delays and/or stoppages. Similarly, an increased demand forecast could lead to a raw material shortage. One possible mitigation strategy is to build sufficient inventory to ensure continuous product supply. However, large inventories increase the cost of production and the risk of scrapping raw material lots that exceed their shelf life before they can be used.
Diversification and redundancy of raw material supplies by qualification of new raw material sources ensure a geographic footprint of manufacturers providing flexibility and supply resiliency. However, use of alternative raw materials may require approvals from multiple health authorities. Waiting for approvals can significantly delay implementing a change, and the timelines vary between regions, adding further complexity to supply management. For example, implementation of an alternative vial would typically require 4 to 6 months for approval in the EU and US but more than 18 months in other countries. In some cases, to meet the forecast, DP manufacturers manufacture at risk while waiting for approvals for second-source supply.
During the pandemic, the pharmaceutical industry faced challenges in the production of COVID-19 therapeutics and vaccines to meet global demand, as well as mitigation of drug shortages for non-COVID-19-related products, without compromising product quality or patient safety. Lessons learned during the pandemic could be leveraged for future procedures and regulatory submission requirements. This article highlights the regulatory expectations of raw materials, the challenges of postapproval changes. and the impact on supply resiliency. Case studies are presented that demonstrate the importance of defining the raw material attributes that are critical to product quality and how this could support increased postapproval flexibility (including the use of ICH Q12 principles).
The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines contain information regarding regulatory requirements for raw materials. There should be a system for evaluating critical suppliers and a specification agreed upon with the supplier and approved by quality. Upon receipt, incoming raw materials should be tested against specifications that include critical attributes, analytical procedures, and acceptance criteria. Additional requirements are described in ICH Q7. The Common Technical Document (CTD) for the Registration of Pharmaceuticals For Human Use: Quality&#;M4Q guidance covers the minimum requirements for submission of raw materials; however, certain regions have additional requirements.
Raw materials used in the manufacture of the DS should be listed in CTD section 3.2.S.2.3, Control of Materials. The name of each material, where it is used in the process, and information on the quality and control should be provided. The material manufacturer is not required for all cases but is often requested by some health authorities for critical materials such as filters. A compendial or multicompendial grade should be listed where applicable; for all noncompendial materials, specifications should be included. Information demonstrating that the quality of the raw materials meets standards appropriate for their intended use should be provided. For example, biologically sourced raw materials may require careful evaluation to establish the presence or absence of deleterious endogenous or adventitious agents.
Per ICH Q11, the potential for material attributes that impact DS critical quality attributes should be identified. Raw materials used near the end of the manufacturing process have greater potential to introduce impurities into the DS than raw materials used upstream; therefore, tighter control of quality should be evaluated. A risk assessment to define the control strategy of raw materials can include an assessment of manufacturing process capability, attribute detectability, and severity of impact. For example, the ability of the DS manufacturing process to remove an impurity or limitations in detectability (e.g., viral safety) should be considered. The risk related to impurities is typically controlled either by raw material specifications or robust purification steps later in the synthesis.
An excipient is formulated with the active pharmaceutical ingredient and is typically not chemically or physically altered prior to use; therefore, all components are likely present in the DP. The intended end use of the excipient should be considered when determining the appropriate regulatory and GMP requirements for the excipient and its manufacturing facility. The quality of the excipients and the container/closure systems should meet pharmacopeial standards, where available and appropriate. Otherwise, suitable acceptance criteria should be established. The use of a noncompendial mate-rial may be considered acceptable with strong scientific justification. For a multicompendial excipient that may be marketed for global use, the DP manufacturer should demonstrate conformance of the excipient to the monograph requirements found in specified compendia.
A description of the DP and its composition is provided in CTD section 3.2.P.1, Description and Composition of the Drug Product. More details regarding the quality of excipients are provided in CTD section 3.2.P.4, Control of Excipients. For the European Medicines Agency (EMA), functional related attributes should also be considered, and it may be necessary to include additional tests and acceptance criteria, depending on the intended use of the excipient (see Appendix). For excipients of human or animal origin, information should be provided regarding adventitious agents in CTD section 3.2.A.2, Adventitious Agents Safety Evaluation. For novel excipients (i.e., excipients used for the first time in a DP or by a new route of administration), full details of manufacture, characterization, and controls, with cross-references to supporting safety data, should be provided according to the DS format in CTD section 3.2.A.3, Novel Excipients.
Additionally, excipients and primary container components may be subject to regional regulatory requirements. For example, the National Medical Products Administration (NMPA) requires registration of high-risk excipients and primary container components using a master file that is referenced by the DP sponsor.
When a drug manufacturer intends to introduce a change, the potential impact on the process and product quality must be assessed. , , A change is classified as major, moderate, or minor depending on its nature and impact. A major change is one that requires submission and approval by a health authority prior to distribution of post-change material. A moderate change is one that typically requires submission to a health authority but may not require approval prior to distribution of post-change material. A minor change is reported to the health authority after implementation and does not require a submission prior to product distribution. The classification helps determine the data required to demonstrate comparability (pre- and post-change) and confirm no adverse impact on product quality.
A formal change control system under the company&#;s pharmaceutical quality system (PQS) is required to evaluate all raw material changes, with established procedures for identification, documentation, review, and approval. A quality risk management system provides assurance to the health authorities that the applicant can ensure process consistency and product quality while continuously monitoring, verifying, and mitigating identified risks. After approval and implementation of the change, there should be an evaluation of the first batches produced post-change.
Health authorities have divergent classifications for changes in terms of risk to product quality and documentation/data requirements. Table 1 shows the classifications assigned (based on published guidance) to three distinct types of raw material changes for biologics (B) and synthetics (S) across six regulators (FDA, EMA, Health Canada, Therapeutic Goods Administration [TGA], Pharmaceuticals and Medical Devices Agency [PMDA], and NMPA) and the World Health Organization (WHO):
Some health authorities do not include all three changes described in their postapproval guidance; for example, the FDA provides guidance for synthetics, but not biologics. Changes not covered need case-by-case management. In addition, submission categories vary between health authorities, making it very challenging to manage the submissions for a raw material change globally. In some guidance documents, changes require associated conditions to be met and documentation/data to be provided in a specified submission category. If a condition cannot be met, then the submission category may be upgraded to a higher category.
Additional examples of postapproval changes for FDA, EMA, Health Canada, TGA, PMDA, NMPA, and WHO are described in detail in the Appendix. The categories in the Appendix assume all conditions are met, required documentation is available for submission, and they are aligned with health agency expectations. The absence of any of the listed documentation should be scientifically justified.
Due to global regulatory requirements, many postapproval changes cannot be implemented until the health authorities have reviewed and approved the change, which can take considerable time. During technical review, additional time and resources may be required to address requests for information from agencies. Because of the lack of harmonization across regions, it is difficult to predict the time that it will take for approval by each health authority. The estimated global approval times for major changes vary considerably&#;from less than 6 months in some major markets to greater than 18 months in others&#;resulting in periods of several years before full global implementation of a change can occur.
This results in a lack of supply chain agility to implement changes when faced with immediate supply shortages. Managing a strategy to accommodate varying global approval timelines is a challenge. Similarly, there are regulatory hurdles to implementing raw material improvements postapproval to proactively improve raw material reliability (e.g., innovative technologies and raw material specification changes enabled through scientific understanding of raw material attributes and their impact on product quality).
Multiple asynchronous reviews of the same information with varying approval timelines across global health authorities result in a more complex supply chain, without improving safety, quality, or efficacy. Currently, a streamlined data package for fast global implementation of a change is unlikely to be accepted due to differing regional data requirements.
The implementation of a global regulatory infrastructure that is harmonized, flexible, and predictable would provide drug manufacturers the agility to expedite raw material supplier qualifications to be better equipped to face raw material challenges while maintaining product quality and supply to patients. The identification of the critical raw material attributes and appropriate setting of specifications is a crucial first step.
Table 1: Comparison of the submission category of three types of raw material changes for synthetics (S) and biologics (B). HealthMinor Type IA
Minor Type 1B
Self-Reportable
Notifications
Partial Change Application
Moderate
Note: Changing the specification of an excipient where the quality control level is not lowered is also moderate (S) except when tightening quality control limits is a minor change (S). In comparison, addition of test item or tightening of limit of specification is moderate for biologics (B)
Not described in the guidance MajorMinor Quality Change
A robust raw material control strategy can be achieved with an attribute-focused approach to identify critical material attributes. This approach facilitates the development of science-based raw material specifications and phase-appropriate decisions across the life cycle of a material. It is important to engage in material attribute understanding early in commercial process development when raw materials are being selected. A well-defined material target profile can be used to conduct a material attribute assessment, and based on that profile, a control assessment can be completed. This can be executed in several stages:
The attribute-focused approach enables identifying critical material attributes and developing science-based specifications, which are established based on the intended use of the material and the process requirements; for example, avoiding the use of compendial-grade specifications when noncompendial material will suffice or avoiding the use of technical-grade raw materials when more control is required. In addition, having clear user requirements facilitates more informed supplier selection and can support the identification of established conditions (ECs) for raw materials in regulatory filings.
Once the critical material attributes have been established, specifications defined, and suppliers onboarded through the pharmaceutical manufacturer's quality management system, raw material performance can be monitored using attribute data analytics. This enables the predictive assessment of raw material variation, identification of the source of variability, and implementation of proactive mitigations strategies to prevent failures.
Regulatory submissions preferably include only the critical material attributes. For postapproval raw material changes, the material target attribute profile can facilitate a strong scientific justification based on the knowledge and understanding of the process and the critical material attributes. Some examples of noncritical details include registering trade names, listing part/catalog numbers, and information included in the supplier certificate of analysis that is not relevant to ensure product quality. Registration of these details may limit options of second sourcing, especially in the worst-case scenario when a supplier discontinues a material.
ICH Q12 helps streamline postapproval change implementation by establishing harmonized change categorization, including the identification of the portions of an application requiring a submission if changed postapproval. The level of submission category for a change is determined by the level of risk associated with making the change. ICH Q12 provides a framework to enable the modification of some submission categories for changes based on scientific understanding and the level of risk associated with the change.
It includes regulatory tools such as ECs, postapproval change management protocols, and the product life-cycle management document to enhance the manufacturer&#;s ability to manage chemistry, manufacturing, and controls (CMC) changes effectively under the company&#;s PQS. Adoption of the principles of ICH Q12 could result in fewer postapproval submissions and the ability to implement more changes prior to notification.
According to ICH Q12, &#;ECs are legally binding information&#; within an application considered necessary to assure product quality. Any change to an EC requires a submission to the health authority. Identifying ECs enables a risk-based framework, allowing the use of scientific knowledge and risk mitigation to justify the submission category of a change.
The number of ECs for a raw material, how narrowly they are defined, and the associated submission category depend on several factors:
In general, enhanced knowledge and understanding of the relationship between raw material attributes, process parameters, and product quality enable the identification of parameters critical to product quality, leading to a reduction in the number of ECs. For example, employing a performance-based approach to development can demonstrate that a material attribute that was initially considered potentially critical (in a parameter-based approach) is not actually critical and has no impact on product quality.
A decision tree (Figure 2) was modified from ICH Q12 that illustrates the stepwise approach to identifying ECs for raw material attributes and the as-sociated submission categories (in the context of process parameters). For parameters that are not ECs, postapproval changes are not reported.
Overall, agreement with regulators on the ECs and associated submission categories can reduce the number of postapproval submissions to only the changes most critical to ensuring product quality. This provides more flexibility to implement changes and thus the ability to react more quickly to supply chain challenges. In the long term, a collaboration between regulators and industry stakeholders to develop and implement harmonized guidelines for raw materials would help address flexibility challenges, prevent delays in implementing process improvements, and ensure that both regulator and industry resources are devoted to the most critical issues.
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