Author: DR ANTHONY MELVIN CRASTO Ph.D
In March 2011, the European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA) launched, under US-EU Confidentiality Arrangements, a joint pilot program for the parallel assessment of applications containing Quality by Design (QbD) elements.
The aim of this program was to facilitate the consistent implementation of QbD concepts introduced through International Council for Harmonisation (ICH) Q8, Q9 and Q10 documents and harmonize regulatory decisions to the greatest extent possible across the two regions.
To facilitate this, assessors/reviewers from US and EU exchanged their views on the implementation of ICH concepts and relevant regulatory requirements using actual applications that requested participation into the program. The program was initially launched for three years. Following its first phase, both agencies agreed to extend it for two more years to facilitate further harmonization of pertinent QbD-related topics.
The program officially concluded in April 2016. During this period, the agencies received 16 requests to participate. One submission was rejected because the approach presented was not limited to QbD applications, and another application was not reviewed because it was never filed by the applicant.
In total, two Marketing Authorisation Applications (MAA)/New Drug Applications (NDA), three variation/supplements and nine scientific advice applications were evaluated under this program. One MAA/NDA was assessed under the parallel assessment pathway, with the rest following the consultative advice route. Based on the learnings during the pilot, FDA and EMA jointly developed and published three sets of Question and Answer (Q&A) documents.
These documents also addressed comments from the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), which participated as an observer, offering input to further facilitate harmonization. The objective of these Q&A documents was to generate review guides for the assessors/reviewers and to communicate pilot outcomes to academia and industry.
Additionally, these documents captured any differences in regulatory expectations due to regional requirements, e.g. inclusion of process validation information in the dossier. The following topics were covered in each of the three Q&A documents: –
Q&A (1) published on Aug 20, 2013 included the following topics: (a) Quality target product profile (QTPP) and critical quality attributes (CQA), (b) Criticality, (c) Level of detail in manufacturing process descriptions, and (d) QbD for analytical methods1 –
Q&A (2) published on Nov 1, 2013 on Design Space Verification, that included definition, presentation, justification (including potential scale-up effects) and verification of design spaces both for active substances and finished products2 –
Q&A (3) published on Dec 19, 2014 included the following topics: (a) Level of detail in the dossier regarding Risk Assessment (RA), (b) Level of detail in the dossier regarding Design of Experiments (DOE) and Design Space3 R
Additionally, the FDA-EMA pilot provided the agencies an opportunity to harmonize regulatory expectations for the following precedent-setting applications that were reviewed under the consultative advice pathway: – The first continuous manufacturing (CM) based application submitted to both agencies.
Based on the learnings from this application, the following areas related to CM were harmonized: batch definition; control of excipients; material traceability; strategy for segregation of nonconforming material; real-time release testing (RTRT) methods and prediction models; and good manufacturing practice (GMP) considerations for RTRT, validation strategy, models, and control strategy. – A post approval supplement that included a broad based post-approval change management plan/comparability protocol.
Both agencies were harmonized on the expected level of detail in the protocol and considerations for implementation of a risk based approach to evaluate the changes proposed in the protocol. In line with the scope of the QbD pilot program, joint presentations of key findings were publically presented and discussed with stakeholders at different conferences.
These included the Joint EMAParenteral Drug Association QbD workshop4 organized in 2014 which also included participation from FDA and PMDA.
Overall, it is concluded that, on the basis of the applications submitted for the pilot, there is solid alignment between both Agencies regarding the implementation of multiple ICH Q8, Q9 and Q10 concepts. The FDA/EMA QbD pilot program opened up a platform for continuous dialogue which may lead to further communication on areas of mutual interest to continue the Agencies’ support for innovation and global development of medicines of high quality for the benefit of patients.
Both agencies are currently exploring potential joint activities with specific focus on continuous manufacturing, additional emerging technologies, and expedited/accelerated assessments (e.g. PRIME, Breakthrough). Additionally, EMA and FDA are hosting experts from each other’s organisations to facilitate dialog and explore further opportunities.
References: 1. EMA-FDA pilot program for parallel assessment of Quality-by-Design applications: lessons learnt and Q&A resulting from the first parallel assessment http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/08/WC500148215.pdf
2. FDA-EMA Questions and Answers on Design Space Verification http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/11/WC500153784.pdf
3. FDA-EMA Questions and answers on level of detail in the regulatory submissions http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/12/WC500179391.pdf
4. Joint European Medicines Agency/Parenteral Drug Association quality-by-design workshop http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2013/12/event_detai l_000808.jsp&mid=WC0b01ac058004d5c3
EMA publishes Q&A on Health Based Exposure Limits – Does the 1/1000 dose criterion come again into play in Cleaning Validation?
In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. This publication triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now a draft of a Q&A paper from the EMA provides some concretisation.
In 2014 the European Medicines Agency (EMA) issued the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. As mentioned in the publication itself, this document triggered a discussion about the Permitted Daily Exposure (PDE) values in the Pharmaceutical and even in the API Industry, especially regarding crosscontamination and cleaning validation. Now, the draft of a question & answer paper from the European Medicines Agency provides some concretisation of the guideline.
The document altogether comprises five pages with 14 questions and answers.
The questions – and even more the answers – are very interesting, as shown in question 1 already: Do companies have to establish Health Based Exposure Limits (HBELs) for all products?
The answer is: Yes, but there are references to question 2 and 4 (and their respective answers). Question 2 clarifies what products/active substances are considered as highly hazardous. There are, among others, 5 groups listed, which products should be classified as highly hazardous (e.g.compounds with a high pharmacological potency, daily dose < 1 mg/day (veterinary dose equivalent 0.02 mg/kg)). For highly hazardous substances the answer yes in question 1 is expected. Even more interesting is the link to question and answer 4: Can calculation of HBELs be based on clinical data only (e.g. 1/1000th of the minimum therapeutic dose)? And the answer is yes, but only at designated circumstances. This means the products should have a favourable therapeutic index (safety window) and the pharmacological activity would be the most sensitive/critical effect.
Some further clarification regarding LD 50 is provided in Question 5 and the respective Answer: The use of LD 50 to determine health based limits is not allowed.
There are also more questions and answers regarding Veterinary Medicinal Products, the inspection of the competence of the toxicology expert developing HBELs, Occupational Exposure Limits, cleaning limits, Investigational Medicinal Products and paedric medicinal products and about Cross Contamination. Details will follow.
The document is still a draft and the industry has the opportunity to comment it until the end of April 2017. Let´s see what the final version will bring.
Please also see the draft Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’on the EMA website.
At ECA´s Cleaning Validation Course, 9-10 February 2017 in Heidelberg, Germany the EMA Q&A draft will also be discussed.
///////////EMA, Q&A , Health Based Exposure Limits, 1/1000 dose , criterion, Cleaning Validation,
Apr 13, 2014 – Thailand has its own drug registration format and also follows. ASEAN CTD. … Transparency in the regulatory authorities of member countries.
THAILAND PHARMACEUTICAL REGISTRATION AND APPROVAL
The Thai FDA (TFDA), one of several agencies under the Ministry of Public Health (MPH), is the regulatory body administering drugs in Thailand. The Drug Control Division of the TFDA is responsible for registration, licensing, surveillance, inspection and adverse event monitoring for all pharmaceuticals and pharmaceutical companies in Thailand. Foreign pharma companies dominate the Thai drug market. Due in part to trade negotiations, regional harmonization and positive economic trends, the pharmaceutical market in Thailand is predicted to double by 2022.There are several versions of the Drug Act currently in effect, and the Thai government is working on a revised version with updated regulations. Under the current laws, pharmaceuticals are categorized as either traditional or modern medicines, with different applications and oversight. Modern medicines are subdivided into three categories, each of which has separate registration requirements. Licenses currently do not require renewal.
FIRST ASEAN COUNTRY WITH A NATIONAL eCTD PROGRAM
Thai FDA intends to accept dossier in eCTD format: The Drug Regulatory Authority of Thailand (Thai FDA) has initiated the acceptance of Pilot eCTD from October 2014.Read More
Step to be followed to submit eCTD application
Regulatory Scientist at Kinapse
A) Prepare Application to get a eSubmission Identifier for every application issued. A request to the THAI FDA online service should be submitted to obtain an eSubmission identifier which will require following details.
- Licensee Number
- Description of Application
- Dosage Form
- INN or Generic Name
- WHO ATC Code
- Sequence Type
- Application form
- CPP (In case of Importer)
The eSubmission Identifier will be issued within 10 days of application. The Applicant must then make an appointment for submission within 30 days.
B) Prepare valid application along with validation reports as per country (Thailand) specific requirement with regional eSubmission Identifier provided.
The M1 requirements to be kept in consideration while compiling the Submission.
- Enhanced granularity for each sections
- Country code is not required in filenames
- Information relating to orphan market is not mandatory
- For LCM (Life cycle management) submissions the Operation attribute should be “Replace” in Tracking Table
- Validation report should be submitted along with the sequence
- 1.3.1 Product Information has been broken down into three specific sections for Labelling, SPC and the Package leaflet. No other product types are expected. If one file is submitted for this section, it should be submitted under 18.104.22.168 Labelling.
- 22.214.171.124 Package Leaflet has been broken down into language sections for English, Thai and Other languages.
- It is recommended that separate files should be submitted for each language.
- Applicants can re-use the content submitted in other regions (including STF).
- The identifier is a combination of a letter and seven digits.
- Working documents are not needed and do not need to be provided within the eCTD framework for Thailand
- Section 1.5.2 “Information for Generic, ‘Hybrid’ or Bio-similar Applications” has been broken down into three sections and given a section number to make expectations and cross referencing clearer.
- Only one file should be provided for 1.6 Environmental Risk Assessment. It is not allowed to provide content in both 1.6.1 and 1.6.2.
- During lifecycle, 1.8.2 Risk management plan should always use the lifecycle operator replace.
C) Dispatch Activity Delivery of the application at Thai FDA in CD/DVD (make an prior appointment with HA at firstname.lastname@example.org
Thai FDA has proposed a set of media formats to be used while submission of eCTD
- (CD-R) i.e. Compact Disc-Recordable
- Digital Versatile Disc-Random Access Memory (DVD-RAM)
- Digital Versatile Disc-Recordable (DVD+R/-R) recorded
Future Aspect-Import: The eCTD will be validated and imported into the THAI FDA Review System
Feedback: Application feedback (if there are problems experienced during the upload) and review of application by Thai FDA
Ensure that you do not use. 1. Double-sided discs 2. Re-writable disc (protection, authenticity and Stability of information cannot
Ensure that you do not use:
- Double-sided discs,
- Re-writable discs (protection, authenticity, and stability of information cannot be guaranteed)
- Compressed or zipped files (except for validation reports)
In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version of the FDA Guideline for Combination Products?
In the beginning of 2015 the FDA has published a draft guideline about GMP for Combination Products. Now the final version has been published. What are the differences between the draft and the final version? In the following you will find an overview:
The final guideline has expanded to now 59 pages (draft: 46 pages). And also the number of footnotes increased from 85 (draft) to 147 (final).
In the table of content there are one new subchapter (II B Quality and Current Good Manufacturing Practice) and one new chapter (VII Glossary). Subchapter III C was expanded to definitions and terminology. In the following the table of content is listed:
A. Definition of a combination product
B. Quality and Current Good Manufacturing Practices
C. Overview of the final rule
D. The role of the lead center and other agency components
III. General Considerations for CGMP Compliance
A. Demonstrating compliance
B. Investigational products
C. Definitions and terminology
D. What CGMP requirements apply to a product or facility?
E. Control of changes to a combination product
IV. What do I need to know about the CGMP requirements specified in 21 CFR 4.4(b)?
A. Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1)
B. Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)
C. Combination products that include biological products and HCT/Ps
V. Application of CGMP requirements to specific types of combination products
A. Prefilled syringe
B. Drug-coated mesh
C. Drug Eluting Stent (DES)
VI. Contact Us
In the introduction it is explicitly stated, that “The final rule did not establish any new requirements”. In a footnote the guideline gives an explanation why the term “legacy” combination product has not been used.
In the new subchapter II B (Quality and Current Good Manufacturing Practice) the guideline mentions, that “the core requirements embedded in these regulations provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. This includes establishing a strong quality management system, using appropriate quality raw materials, establishing robust manufacturing and control procedures based on sound design principles, and detecting and investigating product quality deviations. In addition, these regulations call for ongoing assessment of systems and the implementation of corrective actions where appropriate”.
The final document introduces in Section C the new term “CGMP operating system”. This means the operating system within an establishment that is designed and implemented to address and meet the current good manufacturing practice requirements applicable to the manufacture of a combination product. A clarification about constituent parts of cross-labeled combination products is also implemented. Further, there is a new passage about the choice of the GMP-approach (QS regulation vs drug CGMPs) also regarding a streamlined approach and for companies manufacturing different products. Completely new is the passage with the title “Documentation of CGMP Approach”. Here you can also find hints that manufacturerers with products that have been on the market since before GMP for Combination Products (21 CFR 4) came into operation, have to be compliant too. The guideline requires that the information about the “CGMP operating system” should be shared with FDA investigators in the beginning of an inspection.
In the “Demonstrating compliance” subchapter (III A) there is additional information about crossreferenced approaches (21 CFR 820 vs 21 CFR 211 and vice versa). For investigational products (III B) you can find more detailed information about exemptions from part 820 regarding 21 CFR 820.30 (Design).
In the Definition and terminology section (III D) there are amendments regarding container closure aspects and kits. Section III D (What CGMP requirements apply to a product or facility?) details the responsibility of the owner of a combination product and CAPA procedures in shared facilities.
In section III E. (Control of changes to a combination product) information for single entity and co-packed combination product manufacturers has been amended. The passages in IV A (Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1) with regard to 21 CFR 820 about Management Responsibility, Design Controls, Purchasing Controls and CAPA have been extended – including examples – and “modernised”. Terms like quality oversight and QTTP are now mentioned there. Vice versa the passages with regard to 21 CFR 211, 211.84. 211.103, 211.132, 211.137, 211.165, 211.166, 211.167, and 211.170, (IV B Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)) have also been extended – likewise with examples – and have been “modernised” as well (e.g. parametric release is mentioned).
In the example about prefilled syringes (V A) one can find an amended passsage about Design Controls and a new section about Design History File. In the example about drug-coated mesh (V B) there has also been included a new section about Design History File. In the drug eluting stent example (V. C) there are amendments in the section about 21 CFR 211.184, 21 CFR 211.103 and 21 CFR 211.170. Furthermore all examples comprise editorial changes.
Completely new is the chapter VII (Glossary). The number of references (Chapter VIII) increased to 31 (draft: 19).
There are a lot of changes from the draft to the final document. One chapter (Glossary) and a subchapter ( Quality and Current Good Manufacturing Practices) are new, but there are also new passages and amendments in the final document. Helpful are the examples that have been integrated.
Please also see the Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products for more details.
GMP’s for Early Stage Development of New Drug substances and products
|Description||range of colour|
|identification||conforms to a reference spectrum|
|assay||97–103% on a dry basis|
|impurities||NMT 3.0% total, NMT 1.0% each|
|mutagenic||follow EMA guidelines (pending ICH M7 guidance)|
|inorganic||follow EMA guidelines (pending ICH Q3D guidance)|
|residual solvents||use ICH Q3C limits or other justified limits for solvents used in final synthetic step|
|water content||report results|
|solid form||report results|
|particle size||report results|
|residue on ignition||NMT 1.0%|
“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent
The new EMA “Guideline on the chemistry of active substances” represents the current state of the art in regulatory practice and fits into the context of the ICH Guidelines Q8-11. Find out what information regarding active substances European authorities expect in an authorization application.
A medicinal product authorization application requires comprehensive information on origin and quality of an active substance. What information is required was defined in two Guidelines so far: the Guideline “Chemistry of Active Substances” (3AQ5a) from 1987 and the “Guideline on the Chemistry of New Active Substances” from 2004. Because both Guidelines’ content do not take into account the ICH Guidelines Q8-11 issued in the meantime and do thus not meet the current state of the art in sciences and in regulatory practice, the EMA Quality Working Party (QWP) developed an updated document entitled “Guideline on the chemistry of active substances” (EMA/454576/2016), which was issued on 21 November.
The new Guideline describes the information on new or already existing active substances required in an authorization dossier. In the context of this Guideline “already existing” ingredients are those that are used in a product already authorized in the EU.
In detail the information and data regarding the substance have to be included in the following chapters of the CTD:
3.2.S.1: Nomenclature, information on the structural formula, pharmacological relevant physicochemical properties.
3.2.S.2: Information on the manufacturer(s), contractor(s), testing facilities etc.; description of the manufacturing processes (schematic representation with flow diagram as well as narrative); where appropriate detailed information on alternative manufacturing processes, for recovering of solvents and for routine reprocessing. Information with regard to re-working should not be included in the authorization dossier.
3.2.S.2.3: Information for controlling the material used during the manufacture and for its specification (incl. identity test). This paragraph is more comprehensive in the new Guideline compared with its predecessor and takes into account the requirements of the ICH Guideline Q11. This Guideline comprises requirements for the following materials: materials from biological sources, those used for the chemical synthesis of starting materials, materials from herbal origin, excipients like solvents (incl. water), reagents, catalysts etc.
3.2.S.2.4: Information on critical process steps (the Guideline comprises examples for these critical steps) as well as on quality and control of isolated intermediates within the synthesis steps. All information has to be provided with the appropriate justifications.
3.2.S.2.5: Information on Process Validation
3.2.S.2.6: Information on the development of the manufacturing process. Here all changes have to be described that were performed during the various phases (pre-clinical, clinical, scale-up, pilot and possibly production phase) of the process for new active substances. For already existing active substances available in production scale no information on process development is needed.
3.2.S.3: Information on Characterisation. Comprehensive information on the elucidation of the structure of the active substance, its physico-chemical properties and its impurities profile have to be provided. Further, the mutagenic potential of degradation products has to be considered. The analytical methods have to be described and their suitability has to be justified.
3.2.S.4: Information on the control of active substances. The analytical procedures and their validation have to be described. Data for the analytical method development should be provided if critical aspects of the analysis regarding the active substance’s specification need to be clarified. Analytical data are necessary for batches for pre-clinical and clinical studies as well as for pilot batches which are not less than 10% of the maximum production scale. The substance’s specification and its control strategy have to be justified on the basis of data from the pre-clinical and clinical phase and, if available, from the production phase.
3.2.S.5: Information on reference materials. If no Chemical Reference Substances (CRS) of the European Pharmacopoeia – counting as completely qualified reference standards – are used, comprehensive information on the analytical and physico-chemical characterization are required even for established primary standards.
3.2.S.6: Information on Container Closure System. Here a brief description is sufficient. However, if a Container-/Closure System is critical for the substance’s quality, its suitability has to be proven and justified. A reference to stability data can be used as supporting information.
3.2.S.7: Information on Stability. A detailed description of the stability studies carried out and the protocol used as well as a summary of the results are expected. Information on stress studies and conclusions on storage conditions and re-test dates or expiry dates are also to be made. This does not apply to substances monographed in the European Pharmacopoeia. If no re-test period or expiry date of batches on the production scale is available at the time of submission of the application, a stability commitment has to be attached with a post-approval stability protocol. The analytical methods have to be described.
The Guideline’s provisions also apply to an Active Substance Master File (ASMF) or to a Certificate of Suitability (CEP). They apply to active substances that have undergone development in a “traditional” way or according to the “enhanced” approach. The provisions of the ICH Guidelines Q8-11 have to be taken into account.
The Guideline is not applicable to active substances of herbal, biological and biotechnological origin as well as to radiolabelled products and radiopharmaceuticals.
The Guideline “Guideline on the chemistry of active substances” (EMA/454576/2016) becomes effective six months after issuing, which means in May 2017.
///////////////EMA, Guideline, chemistry of active substances
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.
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