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The ICH Q11 Guideline describing approaches to developing and understanding the manufacturing process of drug substances was finalised in May 2012. Since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experience has shown that there is some need for clarification. Thus the Q11 Implementation Working Group recently issued a Questions and Answers Document.
The ICH Q11 Guideline describes approaches to developing and understanding the manufacturing process of drug substances. It was finalised in May 2012 and since then the pharmaceutical industry and the drug substance manufacturers had time to get familiar with the principles outlined in this guideline. However, experiences during implementation of these principles within this 4 years period have shown that there is need for clarification in particular with regard to the selection and justification of starting materials.
On 30 November 2016 the ICH published a Questions and Answers document “Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)” which was developed by the Q11 Implementation Working Group. This document aims at addressing the most important ambiguities with respect to starting materials and at promoting a harmonised approach for their selection and justification as well as the information that should be provided in marketing authorisation applications and/or Drug Master Files.
In the following some examples of questions and answers from this document:
ICH Q11 states that “A starting material is incorporated as a significant structural fragment into the structure of the drug substance.” Why then are intermediates used late in the synthesis, which clearly contain significant structural fragments, often not acceptable as starting materials?
The selection principle about “significant structural fragment” has frequently been misinterpreted as meaning that the proposed starting material should be structurally similar to the drug substance. However, as stated in ICH Q11, the principle is intended to help distinguish between reagents, catalysts, solvents, or other raw materials (which do not contribute a “significant structural fragment” to the molecular structure of the drug substance) from materials that do. … The presence of a “significant structural fragment” should not be the sole basis for of starting material selection. Starting materials justified solely on the basis that they are a “significant structural fragment” probably will not be accepted as starting materials by regulatory authorities, as the other principles for the appropriate selection of a proposed starting material also require consideration.
Do the ICH Q11 general principles for selection of starting materials apply to processes where multiple chemical transformations are run without isolation of intermediates?
Yes. The ICH Q11 general principles apply to processes where multiple chemical transformations are run without isolation of intermediates. In the absence of such isolations (e.g., crystallization, precipitations), other unit operations (e.g., extraction, distillation, the use of scavenging agents) should be in place to adequately control impurities and be described in the application. The drug substance synthetic process should include appropriate unit operations that purge impurities.
The ICH Q11 general principles also apply for sequential chemical transformations run continuously. Non isolated intermediates are generally not considered appropriate starting materials.
Is a “starting material” as described in ICH Q11 the same as an “API starting material” as described in ICH Q7?
Yes. ICH Q11 states that the Good Manufacturing Practice (GMP) provisions described in ICH Q7 apply to each branch of the drug substance manufacturing process beginning with the first use of a “starting material”. ICH Q7 states that appropriate GMP (as defined in that guidance) should be applied to the manufacturing steps immediately after “API starting materials” are entered into the process … . Because ICH Q11 sets the applicability of ICH Q7 as beginning with the “starting material”, and ICH Q7 sets the applicability of ICH Q7 as beginning with the “API starting material”, these two terms are intended to refer to the same material.
ICH Q7 states that an “API Starting Material” is a raw material, intermediate, or an API that is used in the production of an API. ICH Q7 provides guidance regarding good manufacturing practices for the drug substance; however, it does not provide specific guidance on the selection and justification of starting materials. When a chemical, including one that is also a drug substance, is proposed to be a starting material, all ICH Q11 general principles still need to be considered.
With the recent publication of this draft Q&A Document with the complete title “Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Questions and Answers (regarding the selection and justification of starting materials)” on the ICH website it reached Step 2b of the ICH Process and now enters the consultation period. Comments may be provided by e-mailing to the ICH Secretariat at email@example.com.
QbD Takes a Step Forward with ICH Q11
Ever since the FDA issued its landmark guidance Pharmaceutical GMPs-A Risk Based Approach in 2004, the industry has been struggling with how to demonstrate process understanding as a basis for quality. Bolstered by guidance from ICH, specifically Q6-Q10, the pieces have long been in place to build a solution that is philosophically consistent with these best practice principles. Even so, the evolution to process understanding as a basis for quality has been slow. Pressure to accelerate this transformation spiked in 2011 when the FDA issued its new guidance on process validation that basically mandated the core components of ICH Q6-10 as part of Stages 1 and 2. To be fair, enforcement has been uneven and that fact has further impeded adoption, with the compliance inspectors themselves struggling to acquire the necessary skills to fully evaluate statistical arguments of process control and predictability.
One area debated since 2008 is the application of GMPs and demonstration of control for drug substances. Drug substance suppliers and drug product manufacturers have used the tenets of ICH Q7A as the foundation for deciding where GMPs can be reasonably implemented, to establish the final intermediate (FI) and the regulatory starting material (RSM). However, the ability to support the quality of the drug substance has a profound impact on the ability to defend the drug product quality. In the last few years it has become apparent that it was not reasonable to apply the same requirements for drug products to drug substances because the processes can be markedly different. In response to this need, the ICH issued a new guidance; Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities). The key ICH documents that impact Q11 are shown in Figure 1.
Figure 1. Guidances Impacting ICH Q11.
The FDA formally adopted ICHQ11 in November 2012 and its purpose is two-fold. First, it offers guidance on the information to provide in Module 3 of the Common Technical Document (CTD) Sections 3.2.S.2.2 – 3.2.S.2.6 (ICH M4Q). Second, and perhaps most importantly, it attempts to clarify the concepts defined in the ICH guidelines on Pharmaceutical Development (Q8), Quality Risk Management (Q9), and Pharmaceutical Quality System (Q10) as they pertain to the development and manufacture of drug substances.
What makes ICH Q11 so important is its emphasis on control strategy. This concept was introduced in ICH Q10 as “a planned set of controls, derived from current product and process understanding that assures process performance and product quality.”
Within the drug product world, the control strategy concept has been elusive as industry grapples with moving from a sample-and-test concept of quality to one of process understanding and behavior. This concept is even more removed for drug substance manufacturers and, in some cases, is more difficult to implement. But Q11 is much more than a mere framework for control strategy. The guidance is structured very similarly to the concepts discussed in the new 2011 Process Validation guidance. Looking closely, Q11 addresses:
• Product Design/Risk Assessment/CQA Determination
• Defining the Design Space and establishing a control strategy
• Process validation and analysis
• Information required for Sections 3.2.S.2.2 – 3.2.S.2.6 of the eCTD
• Lifecycle management
Product design/Risk assessment/CQA determination
Within the context of process development, the guidance defines similar considerations to those defined in the Stage 1 activity of Process Validation. Understanding the quality linkage between the drug substance’s physical, chemical, and microbiological characteristics, and the final drug products’ Quality Target Product Profile (QTPP), is the primary objective of the product and process design phase. The product’s QTPP is comprised of the final product Critical to Quality Attributes (CQAs). Identifying the raw material characteristics of the drug substance that can impact the drug product is a critical first step in developing a defensible control strategy. Employing risk analysis tools at the outset can help focus the process development activities upon the unit operations that have the potential to impact the final product’s CQAs. In the case of biological drug substances, any knowledge regarding mechanism of action and biological characterization, such as studies that evaluate structure-function relationships, can contribute to the assessment of risk for some product attributes.
Drug substance CQAs typically include those properties or characteristics that affect identity, purity, biological activity, and stability of the final drug product. In the case of biotechnological/biological products, most of the CQAs of the drug product are associated with the drug substance and thus are a direct result of the design of the drug substance or its manufacturing process. When considering CQAs for the drug substance, it is important to not overlook the impact of impurities because of their potential impact on drug product safety. For chemical entities, these include organic impurities (including potentially mutagenic impurities), inorganic impurities such as metal residues, and residual solvents.
For biotechnological/biological products, impurities may be process-related or product-related (see ICH Q6B). Process-related impurities include: cell substrate-derived impurities (e.g., Host Cell Proteins [HCP] and DNA); cell culture-derived impurities (e.g., media components); and downstream-derived impurities (e.g., column leachable). Determining CQAs for biotechnology/biological products should also include consideration of contaminants, as defined in Q6B, including all adventitiously introduced materials not intended to be part of the manufacturing process (e.g., viral, bacterial, or mycoplasma contamination).
Defining the design space and establishing a control strategy
ICH Q8 describes a tiered approach to establishing final processing conditions that consists of moving from the knowledge space to the process design space and finally the control space. ICH Q8 and Q11 define the Design Space as “the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.” In the drug product world the terminology typically applied to the design space is the Proven Acceptable Range (PAR) that used to equate to the validated range.
Here is why this is important: the ability to accurately assess the significance and effect of the variability of material attributes and process parameters on drug substance CQAs, and hence the limits of a design space, depends on the extent of process and product understanding. The challenge with drug substance processes is where to apply the characterization. ICH Q7A recognizes that upstream of the RSM does not require GMP control. The design space can be developed based on a combination of prior knowledge, first principles, and/or empirical understanding of the process. A design space might be determined per unit operation (e.g., reaction, crystallization, distillation, purification), or a combination of selected unit operations should generally be selected based on their impact on CQAs.
In developing a control strategy, both upstream and downstream factors should be considered. Starting material characteristics, in-process testing, and critical process parameters variation control are the key elements in a defensible control strategy. For in-process and release testing criteria the resolution of the measurement tool should be considered before making any conclusions.
ICH Q11’s description of process validation mimics the same description in ICH Q7A but offers up an alternative for continuous verification that mirrors the concepts in ICH Q8 and the new process validation guidance. As mentioned, the enforcement of the new guidance by the FDA has been uneven, but positioning the process validation to satisfy the new guidance requires the drug substance manufacturer to formally implement characterization and validation standards, just as a drug product manufacturer would be required to do.
The quality system elements and management responsibilities described in ICH Q10 are intended to encourage the use of science-based and risk-based approaches at each lifecycle stage, thereby promoting continual improvement across the entire product lifecycle. There should be a systematic approach to managing knowledge related to both drug substance and its manufacturing process throughout the lifecycle. This knowledge management should include but not be limited to process development activities, technology transfer activities to internal sites and contract manufacturers, process validation studies over the lifecycle of the drug substance, and change management activities.
The new ICH Q11 guidance represents the most recent example of the FDA’s commitment to the principles of QbD to define an integrated framework for implementing the principles of ICH Q6-Q10. Although the guidance does not mandate adopting ICH Q8, the considerations required to create a defensible control strategy require a much higher level of process understanding than the conventional approach of sample and test, once the foundation of product development. Defining the requirements is another example of where the FDA is going in terms of expectations for drug substance and drug product understanding. If effectively enforced, this can be a significant step forward, pushing the industry toward a QbD philosophy for process and product development.
/////////Selection, justification, starting materials, ICH Q11 , ich, qbd
Generics: The US Food and Drug Administration (FDA) recently published a new Guidance regarding Prior Approval Supplements (PAS). Read more about FDA´s Guidance for Industry “ANDA Submissions – Prior Approval Supplements Under GDUFA“.
On October 14, 2016, the US Food and Drug Administration (FDA) published a new Guidance regarding Prior Approval Supplements (PAS).
FDA says that “this guidance is intended to assist applicants preparing to submit to FDA prior approval supplements (PASs) and amendments to PASs for abbreviated new drug applications (ANDAs)”.
Specifically, the guidance describes how the Generic Drug User Fee Amendments of 2012 (GDUFA) performance metric goals apply to:
- A PAS subject to the refuse-to-receive (RTR) standards;
- A PAS that requires an inspection;
- A PAS for which an inspection is not required;
- An amendment to a PAS;
- Other PAS-related matters.
GDUFA is designed to speed the delivery of safe and effective generic drugs to the public and reduce costs to industry. That requires that FDA and human generic drug manufacturers meet certain requirements and commitments. “FDA committed to review and act on a certain percentage of PASs within a specified period from the date of submission for receipts in fiscal year (FY) 2015 through FY 2017. The percentage of PASs that FDA has committed to review and act on increases with each fiscal year; the deadlines for review also depend on whether consideration of a PAS requires an inspection.”
Changes to an approved application:
The criteria laid down in FDA regulations for submitting information as a PAS (major change), as a Changes Being Effected-Supplement (CBE-supplement, moderate change), or in an annual report (minor change) were not changed by GDUFA.
Timelines depending on inspections for PAS submissions:
The GDUFA goal date for a PAS depends on whether the PAS requires an inspection. If a PAS does not require an inspection, the goal date is 6 months from the date of submission; but if a PAS requires an inspection, the goal date is 10 months from the date of submission. An initial goal date of 6 months occasionally may change to a 10-month goal date if, during the review, FDA determines an inspection is necessary. If an amendment is made to a PAS, the GDUFA goal date associated with that PAS may be revised. FDA strongly recommends that, at the time of submission, a supplement should be complete and ready for a comprehensive review.
Submission of Supplements:
The following information should be provided on the first page of the PAS:
- A statement indicating whether the PAS is for a new-strength product;
- A statement indicating whether the submission is an amendment to a PAS, and if so the corresponding tier classification;
- A statement indicating whether the PAS contains any manufacturing or facilities changes;
- A list of the specific review disciplines to review the PAS (Chemistry, Labeling, DMF, Bioequivalence, Microbiology, or Clinical);
- If expedited review is requested, the label Expedited Review Request should be placed prominently at the top of the submission. The submission should include a basis for the expedited review request.
It is possible to submit multiple PASs for the same chenge as “grouped supplements”. These are submitted to ANDAs by a single applicant for the same chemistry, manufacturing, and controls (CMC) change to each application. Because the grouped supplements are being reviewed together, generally they will have the same GDUFA goal date. Although the submissions are considered a group, each supplement in the group is considered its own individual submission and therefore would require a GDUFA PAS fee for each ANDA identified in the group.
- Identify a lead ANDA for a group of PASs (only one fee is paid, or fewer than all the fees for the group are paid);
- For some changes (e.g., widening of an approved specification or introduction of a new API supplier) once a PAS is submitted and approved, subsequent supplements for the same change to other ANDAs may be classified as CBE-30s;
- A comparability protocol submitted in a PAS to an ANDA for a specific drug product, once approved, may justify a reduced reporting category for the same change in subsequent supplements to that ANDA.
If FDA finds that a supplement submitted as a CBE supplement should have been submitted as a PAS, it will notify the applicant. The applicant is not required to withdraw the CBE supplement because when FDA sends a letter explaining that the applicant’s submission is not accepted as a CBE supplement, FDA administratively closes the CBE supplement, and it is considered withdrawn. The applicant may resubmit the supplement as a PAS for FDA approval before distribution of the drug product, along with the required GDUFA user fee. The GDUFA performance metric goals and applicable user fees will apply to that PAS and the GDUFA review clock will start from the date of submission of that PAS.
For more information please see the FDA Guidance for industry “ANDA Submissions – Prior Approval Supplements Under GDUFA“.
///////////Generics, FDA, New Guidance, Prior Approval Supplements
|EMA/ FDA Mutual Recognition Agreement moving forward|
|A possible agreement between the EMA and the US FDA on mutual recognition agreement on drug facility inspections could already be signed in January 2017.|
A possible agreement between the European Medicines Agency EMA and the US Food and Drug Administration FDA on mutual recognition of drug facility inspections could already be signed in January 2017. This is noted in a report of the EU Commission: “The state-of-play and the organisation of the evaluation of the US and the EU GMP inspectorates were discussed. In light of the progress achieved, the conclusion of a mutual recognition agreement of Good Manufacturing Practices (GMPs) inspections by January 2017 is under consideration.”
But, according to the Commission, some issues are still not resolved – like, for example, the exchange of confidential information and the inclusion of veterinary products in the scope of the text.
The “Report of the 15th Round of Negotations for the Transatlantic Trade and Invesment Partnership” summaries the 15th round of negotiations for the Transatlantic Trade and Investment Partnership (TTIP) from 3rd to 7th October 2016 in New York.
////////EMA, FDA, Mutual Recognition Agreement, drug facility inspections
Chapter 5 of the EC GMP Guide for the area of production was updated last year. This chapter contains concrete information about the conditions when testing and sampling of APIs and excipients can be reduced. Read more here about the sections 5.35 and 5.36 of the EU GMP Guide.
Chapter 5 of the EC GMP Guide for the area of production was already updated last year. However, not everybody really knows that it contains concrete information about the conditions when testing and sampling of APIs and excipients can be reduced. Particularly sections 5.35 and 5.36 include requirements and thus show possibilities for a reduction.
Basically, the manufacturers of finished products are responsible for every testing of starting materials as described in the marketing authorisation dossier. Yet, part of or complete test results from the approved starting material manufacturer can be used, but at least their identity has to be tested – as described in the in the marketing authorisation dossier.
If one chooses to outsource the testing activity to the supplier, this has to be justified and documented. Moreover, a few additional measures have to be fulfilled, like:
- Particular attention should be paid to the distribution controls (transport, wholesaling, storage, delivery) to ensure that ultimately the test results are still applicable to the delivered material.
- Performance of risk-based audits at the sites executing the testing and sampling of starting materials to verify the GMP compliance and to ensure that the specifications and testing methods are used as described in the marketing authorisation dossier.
- The certificate of analysis of the manufacturer/supplier of the starting material should be signed by a designated person with appropriate qualifications and experience. The signature confirms the compliance with the agreed product specification.
- The medicinal product manufacturer should have adequate experience in dealing with the starting material manufacturer – including assessment of batches previously received and the history of compliance before reducing own, internal testing.
- At appropriate intervals, the medicinal product manufacturer or another approved contract laboratory has to carry out a full analysis to compare the test results with the results of the certificate of analysis of the material manufacturer or supplier, and thus to check their reliability. In case of discrepancy, an investigation has to be performed and appropriate measures taken. The certificates of analysis cannot be accepted until those measures are completed.
You can access the complete Chapter 5 “Production” of the EU GMP Guide here.
////////Opportunities, Reducing, Sampling, Testing, Starting Materials, EC GMP Guide
New EDQM’s Public Document informs about the Details required in a New CEP Application for already Referenced Substances
A Policy Document recently published by the EDQM describes regulations for referencing already existing CEPs in an application for a new CEP. Read more about how the certificates of an intermediate or starting material have to be used in new applications for a CEP.
When applying for a Certificate of Suitability (CEP) for an API, detailed information has to be provided regarding the synthesis stages, the starting material and the intermediates. In the event that the starting materials or the intermediates are already covered by a CEP, the EDQM has recently published a “Public Document” entitled “Use of a CEP to describe a material used in an application for another CEP”. The document contains regulations on how to reference the “CEP X” of a starting material or an intermediate in the application for the “CEP Y” of an API. The requirements for both scenarios are described as follows:
- CEP X belongs to an intermediate or a starting material within the synthesis route of a substance Y for which a CEP is submitted.
1. The submission must make clear that X is really an intermediate or a starting material and is covered by a valid CEP (“CEP X”). A copy of this CEP X has to be attached.
2. The complete specification described in the CEP X must be the basis for the release of the intermediate or the starting materials X for use in the synthesis of Y.
3. The lifecycle of CEP X is directly coupled with the lifecycle of CEP Y. For example, a revision of CEP X also triggers a revision of CEP Y so that the revised CEP X has to be included to the revision application of CEP Y.
4. If the CEP X looses its validity (e.g. due to expiry or withdrawal) the application for CEP Y has to be updated, for example the CEP of a substance from an alternative source has to be submitted.
5. The application for CEP Y has to include complete details about the supply chain and/ or about all the manufacturing sites involved in the process described on CEP X.
Details about all manufacturing sites involved in the process described in the CEP X will also be mentioned in the annex 1 of the new CEP Y when X is an intermediate for the synthesis of Y. However, this doesn’t apply when X is the starting material for the synthesis of Y.
Please see the Public Document “Use of a CEP to describe a material used in an application for another CEP” for further details.
////////// EDQM, Public Document, New CEP Application, already Referenced Substances
Now online – Stimuli article on the proposed USP General Chapter “The Analytical Procedure Lifecycle “
|Now online – Stimuli article on the proposed USP General Chapter “The Analytical Procedure Lifecycle <1220>”|
|A Stimuli Article to the Revision Process regarding the proposed New USP General Chapter “The Analytical Procedure Lifecycle <1220>” has been published. Read more about the new concept for the lifecycle managment of analytical methods.|
The General Chapters—Chemical Analysis Expert Committee is currently developing a new general chapter <1220> The Analytical Procedure Lifecycle. The purpose of this new chapter will be to more fully address the entire procedure lifecycle and define concepts that may be useful.
A Stimuli article on the proposed General Chapter <1220> has been approved for publication in Pharmacopeial Forum 43(1) [Jan.-Feb. 2017]. USP is providing this Stimuli article in advance of its publication to provide additional time for comments.
In addition to offering a preview of the proposed general chapter, the General Chapters—Chemical Analysis Expert Committee and the Validation and Verification Expert Panel are seeking specific input from users in the pharmaceutical industry regarding the following questions:
- Would a general chapter on the lifecycle approach be valuable?
- Is the information presented herein sufficient for implementation of an analytical procedure under the quality by design (QbD) approach?
- Would incorporation of references to statistical tools, either in this chapter or in another chapter, be valuable?
- Can you provide input or approaches that would improve this proposed general chapter?
The content and scope of the proposed general chapter will be refined on the basis of responses to this Stimuli article. Because stakeholders may have differing views, the objective of this Stimuli article is to identify and build areas of consensus that may be included in <1220>.
The approach is consistent with the concept of quality by design (QbD) as described in International Council for Harmonisation (ICH) Q8-R2, Q9, Q10, and Q11.
In order to provide a holistic approach to controlling an analytical procedure throughout its lifecycle, one can use a three-stage concept that is aligned with current process validation terminology:
- Stage 1: Procedure Design and Development (Knowledge Gathering, Risk Assessment, Analytical Control Strategy, Knowledge Management, Preparing for Qualification)
- Stage 2: Procedure Performance Qualification
- Stage 3: Continued Procedure Performance Verification (Routine Monitoring, Changes to an Analytical Procedure)
A fundamental component of the lifecycle approach to analytical procedures is having a predefined objective that stipulates the performance requirements for the analytical procedure. These requirements are described in the analytical target profile (ATP) which can be considered as analogous to the quality target product profile (QTPP).
The Download Stimuli Article is available on the USP website since October 14, 2016: Proposed New USP General Chapter: The Analytical Procedure Lifecycle <1220>.
Comments will be accepted until March 31, 2017, the end of the comment period for Pharmacopeial Forum 43(1). This Stimuli article provides the framework for the proposed general chapter “The Analytical Procedure Lifecycle <1220>” and describes the current thinking of the USP Validation and Verification Expert Panel which advises the General Chapters—Chemical Analysis Expert Committee with regard to future trends in analytical procedures development, qualification, and continued monitoring.
/////////////Stimuli article, proposed USP General Chapter, The Analytical Procedure Lifecycle, <1220>
Dr. Amrendra Kumar Roy
We would like to share our ~13 yrs of practical experience in the field of product development using statistical tools. But first, what compelled us to pursue six-sigma. Most of us started our career as a process chemist after completing PhD and it was during those initial days we realized the importance of “first time right” during commercialization. This enabled not only first mover advantage but also ensured timely and un-interrupted supply of our products into the market. Another aspect of the process development is its robustness, which ensures sustainable margins in whatever products we manufacture. Above achievement was possible only because of the…
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