ICH Q12: Guideline on Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, 1-2
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New ICH Guidelines:
*ICH Q13* on Continuous Manufacturing &
*ICH Q14* on ATP – QbD (Analytical target profile and quality by design)
New ICH Guidelines: ICH Q13 on Conti Manufacturing and ICH Q14 on AQbD
In a press release from 22 June the International Council for Harmonisation (ICH) has announced that they will prepare new topics for the future. The Assembly agreed to begin working on two new topics for ICH harmonisation:
Analytical Procedure Development and Revision of Q2(R1) Analytical Validation (Q2(R2)/Q14)
Continuous Manufacturing (Q13)
The long anticipated revision of ICH Q2(R1) “Guideline on Validation of Analytical Procedures: Text and Methodology” has been approved and the work plan is scheduled to commence in Q3 2018. It is intended that the new guidelines will be consistent with ICH Q8(R2), Q9, Q10, Q11 and Q12 .
The AQbD approach is very important to collect information in order to get an understanding and control of sources of variability of the analytical procedure by defining the control strategy.
Based on the Analytical Target Profile (ATP) the objective of the test and the quality parameters can be defined. By performing the validation (qualification) in the QbD concept, sufficient confidence can be achieved in order to consistently generate the analytical results that meet the ATP requirements.
So far there has been a lack of an Analytical Development Guideline, which the new ICH Development Guideline is supposed to compensate. Currently analytical procedures are mainly validated according to the classical validation parameters and these procedures mainly focus on HPLC Methods. Therefore this ICH topic has a top priority for the pharmaceutical industry. It is expected that the Revision of the Q2 (R1) Guideline will help to implement new and innovative analytical methods.
For more details please read the complete ICH Press Release (Kobe, Japan, June 2018).
The topic of starting materials has been a vexed topic for some period. Indeed concerns relating to lack of clarity and issues pertaining to practical implementation led the EMA in Sept 2014 to publish a reflection paper—Reflection on the requirements for selection and justification of starting materials for the manufacture of chemical active substances.(10) The paper sought to outline key issues as well as authority expectations; specific areas of interest identified included the following:
Variance in interpretation between applicant and reviewer.
The registration of short syntheses that employ complex custom-made starting materials.
Lack of details preventing authorities being able to assess the suitability of a proposed registered starting material and its associated control strategy.
The questions and answers are aligned to specific sections within the guideline, although all questions are focused specifically on Section 5—Selection of starting material and source material. There are 16 questions in total covering the following aspects:
Significant Structural Fragment: how should this be interpreted
Impact on Impurity profile of final product: this relates to the guidance within Q11 to include all stages that impact on impurity profile of the drug substance. This seeks to clarify what level would be defined as impactful.
Clarification of persistence
How an applicant should determine which steps impact the profile of mutagenic impurities in the drug substance.
Do all steps that involve mutagenic reagents, impurities, or establish regio- or stereochemical configurations, need to be included in the process description?
Clarification of the stated need to describe “enough” of the drug substance manufacturing
Should all the ICH Q11 general principles be considered and met in selecting starting materials?
Application of Q11 principles to telescoped processes
Application of Q11 to linear and convergent syntheses
Starting material specifications: key attributes
Noncommercial starting materials
Differences: Commercially available vs Custom Synthesis
Requirements for justification of commercial availability
Scope: postapproval change–preregistered starting materials
Life cycle management
Starting material Q11 vs Q7 definition: clarification that this is effectively the same
Key points of note include
“Significant structural fragment”: the document highlights the frequent misconception that this means that a proposed starting material should be structurally similar to the drug substance. It makes clear that in fact the intent is simply 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.
Questions 5.2, 5.4, and 5.5 relate to mutagenic impurities. The answers provided should be useful in assisting an applicant in applying the risk based approach defined within ICH M7.(5)Prior to this there was a general misconception that a step that involved a mutagenic impurity needed to be part of the registered process. Such an assertion took no account of the highly reactive nature of such impurities and their propensity to be effectively purged.(12) The answer to question 5.2 makes clear the framework for defining the impact of an MI on the quality of the final drug substance, aligning this directly to M7 and the adoption of the widely applied 30% of the limit principle, i.e. prove levels in the final active drug substance are below 30% of the acceptable limit. The answer to question 5.4. provides a commentary of the actual practical steps involved in assessing the impact of an MI. Importantly within this it contextualizes the actual risk posed by low level MIs with the following important statement
“Such mutagenic impurities and by-products are usually present at much lower concentrations than reagents, solvents, and intermediates. Therefore, the risk that such impurities will carry over significantly into the drug substance from early reaction steps is lower than for reagents, solvents, or intermediates from the same steps.”
In essence, provided any MI associated with a starting material is demonstrably controlled it is not necessary to register stages that simply employ the use of mutagenic reagents.
Another important point addressed within the document is ‘persistency.’ It seeks to make clear that even where an impurity associated with a starting material does impact on the quality of the drug substance that control can be defined at the stage of the starting material. A classic example would be a stereoisomer. General downstream processing would have little impact on levels. In many cases this has led to a view that the step where such an impurity might arise must form part of the registered process, i.e. the stage of introduction of chirality. This now makes clear that, provided this is effectively controlled within the starting material, registration of earlier stages is not required.
The response highlights several key aspects
Another key point made is the need for an applicant to examine steps immediately upstream of those identified as critical and within those upstream to consider if:
They include a unit operation that has been added to the manufacturing process to control specific impurities that would otherwise impact the impurity profile of the drug substance.
The key point made here is that you cannot simply add multiple purification steps prior to a proposed starting material.
Tight control (e.g., within narrow parameter ranges) is required to prevent generation of impurities that would otherwise impact the impurity profile of the drug substance.
Perhaps the most contentious aspect of the response though is the caveat that if having conducted the assessment described and if based on this the result is that only a small number of chemical transformation steps need to be registered, the Q&A document articulates a need to include one or more additional steps. The reasons stated for this needing to be considered are
Due to the risk of contamination arising from a late starting material and the impact this would have on drug substance quality and
The risk of changes made to the route/process for the starting material impacting again on drug substance quality.
1.Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities EMA/CHMP/ CVMP/ SWP/169430/ 2012,http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/11/WC500177735.pdf.
2.ICH Q11 – Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)Q11http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf.
3.Teasdale, A.Regulatory Highlights Org. Process Res. Dev. 2015, 19 ( 4) 494– 498, DOI: 10.1021/acs.oprd.5b00085
4.ICH Q3D Guideline for Elemental Impuritieshttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf.
5.Assessment and Control of Dna Reactive (Mutagenic)Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7(R1) March 2017,http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_R1_Addendum_Step_4_31Mar2017.pdf.
6.ICH Q3A Impurities in New Drug Substanceshttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q3A_R2__Guideline.pdf.
7.ICH Q3B Impurities in New Drug Productshttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3B_R2/Step4/Q3B_R2__Guideline.pdf.
8.Harvey, J.; Teasdale, A.; Fleetwood, A.Management of organic impurities in small molecule medicinal products: Deriving safe limits for use in early development Regul. Toxicol. Pharmacol. 2017, 84, 116– 123,DOI: 10.1016/j.yrtph.2016.12.011
9.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’ (EMA/CHMP/CVMP/SWP/169430/ 2012) .http://www.ema.europa.eu/docs/en_GB/document_library/Other/2017/01/WC500219500.pdf.
10.Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substanceshttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500175228.pdf.
11.ICH guideline Q11 on development and manufacture of drug substances (chemical entities and biotechnological/biological entities) – questions and answershttp://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Q_A_Step_2.pdf.
12.Teasdale, A.Risk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies to Demonstrate Control Org. Process Res. Dev. 2013, 17, 221– 230, DOI: 10.1021/op300268u
13.EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Usehttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/chapter_5.pdf.
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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 firstname.lastname@example.org.
EU requirements for quality of APIs in Marketing Authorisation Application Latest developments Maryam MEHMANDOUST, PhD ANSM, France Current Challenges.http://player.slideplayer.com/3/1327610/
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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However, in presentations and articles discussing design space, not much focus has been given to the key phrase, “assurance of quality”. This does not seem justified, given that guidance documents such as ICH Q8, Q9, Q10, PAT, etc. are inundated with the words “risk” and “risk-based.” For any ICH Q8 design space constructed, surely the core definition of design space begs the question, “How much assurance?” . How do we know if we have a “good” design space if we do not have a method for quantifying “How much assurance?” in a scientifically coherent manner?
Classical multivariate analysis and DoE methodology fall short of providing convenient tools to allow one to answer the question “How much assurance?” There are two reasons for this. One is that multivariate analysis and DoE have historically focused on making inferences primarily about response means. But simply knowing that the response means of a process meet quality specifications is not sufficient to allow one to conclude that the next batch of drug product will meet specifications. One reason for this is that we always have batch-to-batch variation. Building a design space based upon overlapping mean responses will result in one that is too large, harboring operating conditions with a low probability of meeting all of the quality specifications. Just because each of the process mean quality responses meet specification does not imply that the results of the next batch will do so; there will always be variation about these means.
However, if we can quantify the entire (multivariate) predictive distribution of the process quality responses as a function of “input variables (e.g., material attributes) and process parameters”, then we can compute the probability of a future batch meeting the quality specifications. The multivariate predictive distribution of the process quality responses incorporates all of the information about the means, variation, and correlation structure among the response types.
Another, more technically subtle reason, that classical multivariate analysis and DoE methodology do not provide straightforward tools to construct a proper design space is that, beyond inference about response means, they are oriented towards construction of prediction intervals or regions. For a process with multiple critical quality responses, it is awkward to try to use a classical 95% prediction region (which is not rectangular in shape) to compare against a (rectangular) set of specifications for multiple quality responses. On the other hand, using individual prediction intervals does not take into account the correlation structure among the quality responses. What is needed instead is a “multivariate predictive distribution” for the quality responses. The proportion of this predictive distribution that sits inside of the rectangular set of quality specifications is then simply a quantification of “how much assurance”.
Complex manufacturing processes are inherently “stochastic processes”. This means that while such process may have underlying mechanistic model relationships between the input factors and process responses, nonetheless such relationships are embedded with random variation. Conceptually, for many complex manufacturing processes, even if “infinitely” accurate measurement devices could be used, such processes would still produce quality responses that vary from batch to batch and possibly within batch. This is why classical multivariate analysis and DoE methodology, which focuses on inference for response means, present an insufficient tool set. This is not to say that such methods are not necessary; indeed they are. However, we need to better understand the multivariate stochastic nature of complex manufacturing processes in order to quantify “how much assurance” relative to an ICH Q8 design space.
The concept of a multivariate distribution is useful for understanding complex manufacturing processes, with regard to both input variables and response variables. Figure 1 shows a hypothetical illustration of the relationships among various input variables and response variables. Notice that some of the input variables and the response variables are described by multivariate distributions. In Figure 1 we have a model which describes the relationships between the input variables, the common cause process variability and the quality responses. This relationship is captured by the multivariate mathematical function f=(f1,…,fr), which maps various multivariate input variables, x, z, e, θ to the multivariate quality response variable, Y=(Y1,…,Yr). Here, x=(x1,…,xk) lists the controllable process factors (e.g. pressure, temperature, etc.), while z=(z1,…,zh) lists process variables which are noisy, such as input raw materials, process set-point deviations, and possible ambient environmental conditions (e.g. humidity).
The variable e=(e1,…,er) represents the common-cause random variability that is inherent to the process. It is natural that z and e be represented by (multivariate) distributions that capture the mean, variation about the mean, and correlation structure of these random variables. The parameter θ = (θ1,…θp) represents the list of unknown model parameters. While such a list can be thought of as composed of fixed unknown values, for purposes of constructing a predictive distribution, it may be easier to describe the uncertainty associated with these unknown model parameters by a multivariate distribution. The function f then transmits the uncertainty in the variables z, e, and θ to the response variables, Y. In other words, the “input distributions” for z, e, and θ combine to produce the predictive distribution for Y through the process model function f.
Figure 1. Multivariate distributions and the role they play in the design space reliability. Here, it is clear that the multivariate predictive distribution associated with the process control values (x = (x1,…, xk) ) results in an unreliable process.
The controllable process factors x can then be used to move the distribution of response variables Y to be better situated within the region bounded by the quality specifications. In Figure 1, the rectangular gray region in the lower left is the region bounded by the quality specifications for “percent dissolved” and “friability” for a tablet production process. Here, one can see that the process operating at operating set point x it not reliable because only about 65% of the predictive distribution is within the region carved out by the quality specifications. (The concentric elliptical contours are labelled by the proportion of the predictive distribution inside of each contour.)
In Figure 2, however, one can see that the operating set point x is associated with a much more reliable process since about 90% of the predictive distribution is within the region carved out by the quality specifications. Situations like that in Figure 2 can then be used to create a design space in the following way: A design space (for a process with multiple critical quality responses) can be thought of as the collection of all controllable process factors (x-points) such that the an acceptably high percentage of the (multivariate) predictive distribution of critical quality responses falls within the region outlined by the (multiple) quality specifications.
Figure 2. Multivariate distributions and the role they play in the design space reliability. Here, it is clear that the multivariate predictive distribution associated with the process control values (x = (x1,…, xk) ) results in a process with a higher reliability.
Slight modifications of the above definition may be needed to accommodate situations involving feedback/feedforward control, etc. But a predictive distribution of the quality responses is required nonetheless in order to address the question of “How much assurance?”
Viewing Figures 1 and 2 shows that one can get a predictive distribution (for the quality responses in Y) if one has access to the various input distributions, in particular the multivariate distribution representing the uncertainty due to the unknown model parameters. But how can one compute the distribution representing the uncertainty due to the unknown model parameters? One possible approach is to use Bayesian statistics.
The Bayesian statistical paradigm provides a conceptually straightforward way to construct a multivariate statistical distribution for the unknown model parameters associated with a manufacturing process. This statistical distribution for the unknown model parameters is known as the “posterior” distribution by Bayesian statisticians. The resulting distribution for Y (in Figures 1 and 2) is called the posterior predictive distribution. This distribution accounts for uncertainty due to common-cause process variation as well as the uncertainty due to unknown model parameters. It also takes into account the correlation structure among multiple quality response types. In addition, the Bayesian approach also allows for the inclusion of prior information (e.g., from previous pilot plant and laboratory experiments). In fact, use of the posterior predictive distribution is an effective way to do process optimization with multiple responses . An excellent overview of these Bayesian methods is given in the recent book Process Optimization: A Statistical Approach . An application of the Bayesian approach to Design space construction is given by this author in .
An alternative approach for obtaining a distribution to represent the uncertainty due to the unknown model parameters involves a concept called “parametric bootstrapping”. This concept is somewhat more transparent than the Bayesian approach. A simple form of the parametric bootstrap approach can be described as follows. First fit your process model to experimental data to estimate the unknown model parameters. Using computer simulation, simulate a new set of (artificial) responses so that you will have new responses similar to the ones obtained from your real experiment. Using the artificial responses, estimate a new set of model parameters. Do this many more times (10,000 say) to obtain many more sets of model parameter estimates. Each of these model parameters (obtained from each artificial data set) will be somewhat different, due to the variability in the data. The collection of all these sets of model parameter estimates forms a bootstrap distribution of the model parameters that expresses their uncertainty. An experiment with a large number of runs (i.e. a lot of information) will tend to have a tighter distribution, expressing the fact that we have only a little uncertainty about the model parameters. But an experiment with only a little information will tend to yield a bootstrap distribution that is more spread out. This is particularly the case, if the common cause variation in the process is also large.
The parametric bootstrap distribution can then be used in place of the Bayesian posterior distribution to enable one to obtain a predictive distribution for the quality responses. This simple parametric bootstrap approach will approximate the Bayesian posterior distribution of model parameters, but it will tend to produce a parameter distribution that is smaller (i.e., a bit too small) than the one obtained using the Bayesian approach. More sophisticated parametric bootstrap approaches are possible  which may result in more accurate approximations to the Bayesian posterior distribution of model parameters.
Unfortunately, the DoE software available in many point-and-click statistics packages does not produce multivariate predictive distributions. It therefore does not provide a way to quantify “How much assurance” one can assign to the Design space. So clearly, easy-to-use software is a current bottleneck to allowing experimenters to produce Design spaces based upon multivariate predictive distributions.
However, there are some software packages that consulting statisticians can use to produce approximate predictive distributions. The SAS statistical package has a procedure call PROC MODEL. (It is part of SAS’s econometric suite of procedures.) This procedure will analyze multivariate response regression models. It has a Monte Carlo option which will produce simulations that allow one to sample from a predictive distribution. This is useful if the process you have can be modeled using PROC MODEL.
The R statistical programming language has functions which will allow the user to do a Bayesian analysis for certain multivariate response regression models. In addition R has a boot function which will allow the user (in conjunction with other R statistical functions) to perform a parametric bootstrap analysis, which can eventually be incorporated into an R program for creating an approximate multivariate predictive distribution. In any case, the SAS and R software does require some statistical sophistication in order to create the appropriate programming steps. Easier to use point-and-click software is still very much needed to lower the computational hurdles for generating multivariate predictive distributions needed for ICH Q8 design space development.
Viewing the multivariate world from our limited three-dimensional perspective is often a challenge. This is no different for a design space involving multiple controllable factors. For the design space definition above, it is convenient to use a probability function, P(x), which assigns a probability (i.e., reliability measure) to each set of process operating conditions, denoted by x = (x1,…, xk). Here, P(x) is the probability that all of the critical quality responses simultaneously meet their specification limits. As stated previously, this probability can be thought of as the proportion of the predictive distribution contained within the region bounded by the quality specifications. The design space is then the set of all x such that P(x) is at least some acceptable reliability value. One can then plot P(x) vs. x to view the design space, provided that the dimension of x (i.e., k) is not too large. A simplified example discussed in  and  is briefly described below.
In an early phase synthetic chemistry study, a prototype design space using a predictive distribution was created for an active pharmaceutical ingredient (API). The (four) quality responses considered were: “% starting material isomer” (<0.15%), “% product isomer” (<2%), “% of impurity #1” (<3.5%), and “% API purity” (>95%). Four controllable experimental factors (x = (x1,…, x4)) were used in a DoE to model how they (simultaneously) influenced the four quality responses. These factors were x1=temperature (oC), x2=pressure (psi), x3= catalyst loading (eq.), and x4=reaction time (hrs).
A Bayesian statistical analysis was used to construct the multivariate predictive distribution for the four quality responses. For the above quality specifications (in parentheses), and for various x-points, the proportion of the multivariate predictive distribution inside the specification region was computed using many Monte Carlo simulations. In other words, for each x-point the corresponding P(x) value was computed. A multipanel contour plot of P(x) vs. the four experimental factors is shown in Figure 3 below. The white regions indicate the regions of larger reliability for simultaneously meeting all of the process specifications. Although these absolute reliability levels are less than ideal, this example is useful for illustration purposes.
Figure 3. Multipanel contour plots of the DS for the early phase synthetic chemistry example. (Used with permission from the Association for Quantitative Management.)
As it turned out, the “optimal” factor-level configurations were such that the associated proportions of the predictive distributions were only about 60% to 70% inside of the quality specification region. Part of the reason for this is that the “input” distributions corresponding to the “unknown model parameters” and the “common cause variation” were too large. A more detailed analysis of this data, conducted in , indicates that if a larger experimental design had been used and the process variation reduced by 30%, the more reliable factor conditions would be associated with reliability measures that were to the 95% level and beyond. This shows the importance of reducing the variation for as many of the process “input” distributions (of the kind shown in Figures 1 and 2) as is possible.
In the case where the dimension of x is not small, a (read-only) sortable spreadsheet could be used to make informed movements within such a design space . While the spreadsheet approach does not provide a high-level (i.e., bird’s eye) view of the design space (as in Figure 3), it does show (locally) how P(x) changes as various controllable factors are changed. In theory, it may also be possible to utilize mathematical optimization routines applied to P(x) to move optimally within a design space whose dimension is not small.
Emphasize efficient experimental designs, particularly for multiple unit operations. For design space construction, clearly it is desirable to have good data that can be efficiently collected. As such, good experimental design and planning is critical. It is particularly useful to have good data that can be efficiently collected across various unit operations in a multi-step process. The performance of one unit operation may depend upon various multiple aspects of previous unit operations. When viewed as a whole, a process may have a variety of interacting variables that span its unit operations. This is an aspect of process optimization and design space construction that requires more research by statisticians and their clients (chemical engineers, chemometricians, pharmaceutical scientists, etc.). Some work has been done  but more is needed. Poor experimental designs can be costly and possibly lead to biases and/or too much uncertainty about unknown model parameters. This is not helpful for developing a good multivariate predictive distribution with which to construct a design space.
Depend upon easy-to-use statistical software for multivariate predictive distributions. As mentioned previously in this article, the availability of easy-to-use statistical software for creating multivariate predictive distributions is a key bottleneck for the development of design spaces that quantify “how much assurance” can be associated with meeting quality specifications. More broadly, it has been shown recently that multivariate predictive distributions can be very useful for process optimization involving multiple responses , . Monte Carlo simulation software applications such as @Risk and Crystal Ball provide point-and-click software for process simulation. However, a key issue that still remains involves producing a multivariate distribution that reflects the uncertainty of unknown model parameters associated with a process. Producing such a distribution is not always statistically simple.
The Bayesian approach provides a unifying paradigm, but the computational issues do require careful assessment of model and distributional assumptions, and in many cases, careful judgement involving convergence of algorithms. The parametric bootstrap approach is more transparent but may produce design spaces that are a bit too large, unless certain technical refinements are brought to bear. Nonetheless, the statistical methods exist to produce good multivariate distributions that represent the uncertainty of unknown model parameters. As always, modeling and inference need to be done with care, using data from appropriately designed experiments.
Use computer simulation to better understand reliability and risk assessments for complex processes. If one can state that they understand a process quantitatively, even a stochastic process, then one should expect that they can simulate such a process reasonably well. Given that many pharmaceutical processes may involve a series of complex unit operations, computer simulation may prove to be helpful for understanding how various process factors and conditions combine to influence multivariate quality responses. With proper care, computer simulation may help process engineers and scientists to better understand the multivariate nature of their multi-step manufacturing procedures. Of course, experimental validation of computer simulation findings with real data may still be needed. In addition, process risk assessments based largely upon judgement (e.g., through tools such as FMEA) can be enhanced through the use of better quantitative methods such as probability measures  (e.g., obtained through computer simulations). The issue of ICH Q8 design space provides a further incentive to utilize and enhance such computer simulation tools.
Have a clear understanding of the processes involved and lurking risks, not just the blind use of mathematical models. We must always keep in mind that our statistical predictions, such as multivariate predictive distributions, are based upon mathematical models that are approximations to the real world environment. How much assurance we can accurately attribute to a design space will be influenced by the predictive distribution, and all of the modeling and input information (e.g. input distributions) that went into developing it. Generally speaking, of course, all decisions and risk measurements based upon statistical methods are influenced to varying degrees by what mathematical modeling assumptions are used, quantifications of design space assurance are fundamentally no different.
However, seemingly good predictive modeling (along with accurate statistical computation) may not be sufficient to provide a design space with long term, high-level assurance of meeting quality specifications. The issue of process robustness is also important, not only for design space construction but in other areas of QbD as well. This issue has many facets and I believe it needs to be given more emphasis in pharmaceutical product development and manufacturing. So as not to go too far on a tangent, I will only briefly summarize some of the issues involved.
In quality engineering, making a process robust to noisy input variables is known as “robust parameter design” (RPD). The Japanese industrial engineer Genichi Taguchi pioneered this approach to quality improvement. The basic idea is to configure the controllable (i.e., non-noisy) process factors in such as way to dampen the influence of the noise process variables (e.g., raw material attributes or temperature/pressure fluctuations in the process). A convenient aspect of the predictive distribution approach to design space, and process optimization in general, is that it provides a technically and computationally straightforward way to do RPD. We simply simulate the nose variable distribution (shown in Figures 1 and 2) and then configure the controllable factors (x-points) to increase the probability of meeting the quality specifications. If the controllable factors are able to noticeably dampen down the influence of the noise variables, typically the probability that the quality responses will meet specifications will increase (assuming that the mean responses meet their specifications). See , , and  for RPD examples involving multivariate predictive distributions.
Less well known, however, are two more subtle issues that can cause problems with predictive distributions. These are lurking variables and heavy-tailed distributions. Process engineers and scientists need to brainstorm and test various possibilities for a change in the process or its inputs that could increase the risk that the predictive distribution is overly optimistic or is not stable over time.
Some predictive distributions may have what are called “heavy tails”. (The degree of “heavy tailedness” is called kurtosis by statisticians.) We need to be careful with such distributions as they are more likely to suddenly produce values far from the center of the distribution, than for a normal (i.e., Gaussian) distribution.
If the process can be simulated on a computer, sensitivity analyses can be done to assess the effect of various shocks to the system or changes to the input or predictive distributions, such as heavier tails. An interesting overview of these two issues and of how quality and risk combine can be found in .
In conclusion, the ability to understand randomness and think stochastically is important as multivariate random variation pervades all complex production processes. Given that we are forced to deal with randomness (in multivariate form, no less), Monte Carlo simulation has become a useful way to gain some insight into the combined effects of controllable and random effects present in a complex production process. (Interested readers may want to visit The American Society for Quality’s web site on Probabilistic Technology available at http://www.asq.org/communities/probabilistic-technology/index.html). Computer simulation can help our intuition for understanding stochastic processes. Such intuition in humans is not always on the mark. We can all be fooled by randomness. See for example the book by Taleb .
1. ICH (2005). “ICH Harmonized Tripartite Guideline: Pharmaceutical Development, Q8.”
2. Peterson, J. J. Snee, R. D., McAllister, P.R., Schofield, T. L., and Carella, A. J., (2009) “Statistics in the Pharmaceutical Development and Manufacturing” (with discussion), Journal of Quality Technology, 41, 111-147.
3. Peterson, J. J. (2004), “A Posterior Predictive Approach to Multiple Response Surface Optimization”, Journal of Quality Technology, 36, 139-153.
4. Del Castillo, E. (2007), Process Optimization: A Statistical Approach, Springer, N.Y.
5. Peterson, J. J. (2008), “A Bayesian Approach to the ICH Q8 Definition of Design Space”, Journal of Biopharmaceutical Statistics, 18, 959-975.
6. Davison, C. and Hinkley, D.V. (1997), Bootstrap Methods and Their Application, Cambridge University Press, Cambridge, UK.
7. Stockdale, G. W. and Cheng, A. (2009), “Finding Design Space and a Reliable Operating Region using a Multivariate Bayesian Approach with Experimental Design”, Quality Technology and Quantitative Management, (to appear).
8. Perry, L. A., Montgomergy, D.C., and Fowler, J. W. (2002), “Partition Experimental Designs for Sequential Processes: Part II – Second Order Models”, Quality and Reliability Engineering International, 18, 373-382.
9. Claycamp, H. G. (2008). “Room for Probability in ICH Q9: Quality Risk Management”, Institute of Validation Technology conference: Pharmaceutical Statistics 2008 Confronting Controversy, March 18-19, Arlington, VA
10. Miro-Quesada, G., del Castillo, E., and Peterson, J.J., (2004) “A Bayesian Approach for Multiple Response Surface Optimization in the Presence of Noise Variables”, Journal of Applied Statistics, 31, 251-270
11. Kenett, Ron S and Tapiero, Charles S. (2009),”Quality, Risk and the Taleb Quadrants” presented at the IBM Quality & Productivity Research Conference, June 3rd, 2009. Available at SSRN: http://ssrn.com/abstract=1433490
12. Taleb, Nassim (2008) Fooled by Randomness: The Hidden Role of Chance in Life and in the Markets, Random House, New York.
/////// ICH Q8 Design Space, Multivariate Predictive Distribution,QA, design space, Parametric bootstrapping, complement Bayesian methods.
ICH Q10 was published in its final version already in 2008. However, today many companies still have problems to understand how to implement ICH Q10 “Pharmaceutical Quality System” into practice. Quality Assurance and GMP are basic requirements which have been implemented for many years in the pharmaceutical industry (including the API industry). So what is needed to demonstrate that a Pharmaceutical Quality System has been implemented? Please read more about the GMP Questions and Answers.
ICH Q10 was published in its final version already in 2008. However, today many companies still have problems to understand how to implement ICH Q10 “Pharmaceutical Quality System” in practice. Quality Assurance and GMP are basic requirements which have been implemented for many years in the pharmaceutical industry (including the API industry). So what is needed to demonstrate that a Pharmaceutical Quality System has been implemented?
ICH offers a set of questions and answers which provide more details about the expectations. They were published in 2009 already but are not well-known by the industry. ICH writes: “When implemented, a company will demonstrate the use of an effective PQS through its documentation (e.g., policies, standards), its processes, its training/qualification, its management, its continual improvement efforts, and its performance against pre-defined key performance indicators (see ICH Q10 glossary on performance indicator). A mechanism should be established to demonstrate at a site how the PQS operates across the product lifecycle, in an easily understandable way for management, staff, and regulatory inspectors, e.g., a quality manual, documentation, flowcharts, procedures. Companies can implement a program in which the PQS is routinely audited in-house (i.e., internal audit program) to ensure that the system is functioning at a high level.”
The questions and answers document also states that there is no certification program in place for a Pharmaceutical Quality System. In addition, ICH provides information about how product-related inspections will differ in an ICH Q8, Q9 and Q10 environment. ICH writes: “In the case of product-related inspection (in particular, preauthorization) depending on the complexity of the product and/or process, greater collaboration between inspectors and assessors could be helpful (for example, for the assessment of development data). The inspection would normally occur at the proposed commercial manufacturing site, and there is likely to be greater focus on enhanced process understanding and understanding relationships, e.g., critical quality attributes (CQAs), critical process parameters (CPPs). The inspection might also focus on the application and implementation of quality risk management principles, as supported by the pharmaceutical quality system (PQS).”
In addition to ICH, regulatory authorities also provide further information. The British Authority MHRA, for example, answers the question: Should a company have a procedure to describe how it approaches QRM related to manufacture and GMP? The answer is: “Yes, the procedure should be integrated with the quality system and apply to planned and unplanned risk assessments. It is an expectation of Chapter 1 that companies embody quality risk management. The standard operating procedure (SOP) should define how the management system operates and its general approach to both planned and unplanned risk management. It should include scope, responsibilities, controls, approvals, management systems, applicability, and exclusions.”
The ECA Academy summarised the most relevant questions and answers from regulators like ICH, EMA, FDA etc in a GMP Questions & Answers Guide which allows readers of the document to search for certain GMP questions. A subject index at the beginning of the document lists the most frequent searched terms.
//////////PQS, ICH, Pharmaceutical Quality System
One and a half year after its publication, the ICH Q3D guideline still raises many questions. The EMA has recently published a guideline draft aiming at clarifying the practical implementation of ICH Q3D. Read more here about what is expected in a marketing authorisation application or in an application for a CEP with regard to risk assessment and the control of elemental impurities in APIs and medicinal products.
The “ICH Q3D Guideline for Elemental Impurities” was published in December 2014 as Step 4 document and released in August 2015 under No EMA/CHMP/ICH/353369/2013 as EMA’s Scientific Guideline. The guideline came into effect in June 2016 for all medicinal products currently underlying a marketing authorisation procedure (new applications).
In the meantime, it became clear that implementing in practice the requirements of this guideline has been so complex and led to some marketing authorisation procedures being delayed. The ICH has already reacted to the situation and published 7 training modules on its website. Moreover, a concept paper announces a question & answer document.
On 12 July 2016, the draft of an EMA’s guideline entitled “Implementation strategy of ICH Q3D guideline” (EMA/404489/2016) was published. The purpose of the document is to provide support for implementing ICH Q3D in the European context.
The draft comprises three chapters addressing the most important elements in relation with the implementation of the ICH Q3D requirements. The chapter “1. Different approaches to Risk Management” starts describing the two fundamental approaches to the performance of a risk assessment and the justification for a control strategy with regard to elemental impurities:
Drug Product Approach
Here, batches of the finished product are scanned by means of analytical (validated!) procedures to develop a risk-based control strategy. If – with this approach – the omission of a routine testing has to be justified, the authority expects a detailed and valid justification though, and not just analytical data from a few batches.
The guideline draft clearly gives its preference to this approach. The respective contribution of the different components of a medicinal product is considered with respect to the potential total impurity profile and compared to the PDE value from the risk assessment. All potential sources of impurity, for example from production equipment or from excipients of natural (mined) origin have to be considered in this assessment. This particularly applies to outsourced APIs; here, all pieces of information available from Active Substance Master Files (ASMFs) or Certificates of Suitability (CEPs) have to be used. Substances with a Ph.Eur. monograph should always comply with the elemental impurities limits of the corresponding monograph.
The chapter “2. Particulars for Intentionally Added Element(s)” deals with the common practice in many organic syntheses to add elements to increase the specificity of the chemical reaction and the yield. It is particularly critical when the last step of an API synthesis just before the end product uses a metal catalyst. In such a case, the authority expects a convincing evidence that the catalyst is purged to levels consistently below the control threshold (<30% of the PDE) by means of appropriate methods. All details about the API synthesis including the fate of the metals intentionally added have to be consistently described and documented in the marketing authorisation application or in the application for a CEP. If the routine testing of an elemental impurity is needed, the API manufacturer may determine a specification. This information will be required by the medicinal product manufacturer for his overall risk assessment.
The chapter “3. ASMF/CEP: dossier expectations and assessment strategy” explains who has to submit the risk assessment necessary for an ASMF or a CEP and how the dossier will be processed by the assessor of the regulatory authority. Basically, two scenarios are possible:
1. The API manufacturer submits a summary of a risk assessment/management for elemental impurities
Such information flows in the overall risk assessment of the medicinal product manufacturer and is assessed by the quality assessor/ CEP assessor within the marketing authorisation procedure. All data and documents used for the risk assessment should also be available for a GMP inspection.
2. The API manufacturer doesn’t perform any risk assessment/ management.
The regulatory authority basically expects a detailed description of the API synthesis including data on all metal catalysts used. This as well as the analytical routine controls on elemental impurities performed by the API manufacturer will also be assessed by the quality assessor/ CEP assessor. Nevertheless, the assessor won’t make a final conclusion in the ASMF or CEP assessment report with regard to the compliance with ICH Q3D. This will be done within the marketing authorisation procedure for the medicinal product.
The guideline draft can be commented on until 12 August 2016.
///////////ICH Q3D, Control of Elemental Impurities, EMA, control of elemental impurities in APIs
A step-wise integrated risk-based approach to determine a control strategy for according to ICH Q3D has to consider data from all kinds of potential sources for elemental impurities in particular from excipients. Read more about the newly created Elemental Impurities Database as a valuable support for performing risk assessments for drug products.
The new ICH Q3D Guideline on Elemental Impurities strongly advocates the use of risk assessments in order to define a final control strategy. Specific challenges appear when risks associated with production equipment, packaging material and excipients have to be determined, and quantified. In particular the contribution of elemental impurities from excipients is not easy to assess due to their big variety and the lack of information from excipient vendors.
Quite recently a pharma consortium started an initiative which aims to collect and share data from pharmaceutical excipients by establishing a database. This Elemental Impurities (EI) Database provides information required for performing a comprehensive risk assessment of a drug product with respect to elemental impurities. Interested companies can contribute to this database by providing information about excipients and may also benefit from this database by taking out information needed for their risk assessments.
The “Impurities Workshop” from 14-16 June 2016 in Heidelberg, Germany provides a comprehensive and practical oriented review of impurities analysis and characterisation in drug substances and drug products. Part III of the workshop on 16 June 2016 is specifically dedicated to Elemental Impurites. In the subsequent post-Conference Workshop on 17 June 2016 the above mentioned EI Database will be explained. The following questions will be discussed:
This post-Conference Workshop is free of charge. It ideally complements the previous parts of the “Impurities Workshop” and can be booked in combination with either Part III or all Parts of the “Impurities Workshop”. As we expect a high interest in this post-Conference Workshop participants joining the “Impurities Workshop” (one day or all three days) will be registered first
methodology provides a risk-based approach to residual solvent
analysis that considers a patient’s exposure to a solvent residue
in the drug product. Solvents have been classified based on their
potential health risks into three main classes:
1. Class 1: Solvents should not be used because of the
unacceptable toxicities or deleterious environmental effects.
2. Class 2: Solvents should be limited because of inherent
3. Class 3: Solvents may be regarded as less toxic and of lower
risk to human health.
Testing is only required for those solvents used in the
manufacturing or purification process of drug substances, excipients
or products. This allows each company to determine which solvents
it uses in production and develop testing procedures that address
their specific needs. It is the responsibility of the drug manufacturer
to qualify the purity of all the components used in the manufacturing
of the drug product. This would pertain to items such as excipients,
of which some contain residual levels of Class 1 solvents by nature
of the manufacturing process and/or nature of the starting materials
(e.g. ethyl cellulose). The new 467 monograph provides an optional
method to determine when residual solvent testing is required for
Class 2 solvents. Each Class 2 solvent is assigned a permitted daily
exposure (PDE) limit, which is the pharmaceutically acceptable
intake level of a residual solvent.
The USP has provided a method for the identification, control,
and quantification of Class 1 and 2 residual solvents. The method
calls for a gas chromatographic (GC) analysis with flame ionization
detection (FID) and a headspace injection from either water or
organic diluent. The monograph has suggested two procedures:
Procedure A G43 (Zebron ZB-624) phase and Procedure B G16
(Zebron ZB-WAXplus) phase. Procedure A should be used first. If
a compound is determined to be above the specified concentration
limit, then Procedure B should be used to confirm its identity.
Since there are known co-elutions on both phases, the orthogonal
selectivity ensures that co-elutions on one phase will be resolved
on the other. Neither procedure is quantitative, so to determine
the concentration the monograph specifies Procedure C, which
utilizes whichever phase will give the fewest co-elutions. Class
3 solvents may be determined by 731-Loss on Drying unless the
level is expected to be >5000 ppm or 50 mg. If the loss on drying
is >0.5 %, then a water deterrmination should be performed using
One of the most important considerations is that, once
implemented, the new method will pertain to all currently marketed
drug products as well as those in development and clinical trials8
United States Pharmacopoeia (USP):
In 1988, the United States Pharmacopoeia (USP) provided
control limits and testing criteria for seven organic volatile impurities
(OVIs) under official monograph 4678
. According to USP, testing
should be conducted only if a manufacturer has indicated the
possible presence of a solvent in a product. Testing may be avoided
when a manufacturer has assurance, based on the knowledge of
the manufacturing process and controlled handling, shipping, and
storage of the product, that no potential exists for specific solvents
to be present and that the product, if tested, will comply with the
accepted limit. Items shipped in airtight containers (such as those
used for food additives) can be considered not to have acquired
any solvents during transportation2
The compounds are chosen based on relative toxicity and only
applied to drug substances and some excipients8
. In addition, a
test for ethylene oxide is conducted if specified in the individual
monograph. Unless otherwise specified in the individual monograph,
the acceptable limit for ethylene oxide is 10 ppm. USP does not
address all other solvents mentioned in the ICH guideline2
In an effort to harmonize with the International Conference
for Harmonization (ICH), the USP has proposed the adoption of
a slightly modified version of ICH (Q3C) methodology, which has
been scheduled for implementation on July 1, 2007. The ICH Q3C
Organic Volatile Impurities
Of the solvents targeted in USP 26 General Chapter 467, only
methylene chloride may appear in bulk pharmaceutical products
manufactured by Pfizer at the Kalamazoo plant. For those products
where OVI testing is required, our material will meet the compendial
limits for methylene chloride and other solvents that may be added
to the target list in the future.
No OVI requirement exists in the USP 26 monograph
for Triamcinolone, but Triamcinolone from Pfizer meets the
requirements of USP 26 General Chapter 467.
Residual solvents in pharmaceuticals, commonly known as
organic volatile impurities (OVIs), are chemicals that are either
used or produced during the manufacture of active pharmaceutical
ingredients (APIs), excipients and drug products1, 2
Organic solvents play an essential role in drug-substance and
excipient manufacture (e.g., reaction, separation and purification)
and in drug-product formulation (e.g., granulation and coating) 3
Some organic solvents are often used during the synthesis of active
pharmaceutical ingredients and excipients or during the preparation
of drug products to enhance the yield, increase solubility or aid
. These process solvents cannot be completely
removed by practical manufacturing practices such as freeze–drying
and drying at high temperature under vacuum. Therefore, some
residual solvents may remain in drug substance material4
the final purification step in many pharmaceutical drug-substance
processes involves a crystallization step, and the crystals thus
formed can entrap a finite amount of solvent from the mother liquor
that may cause degradation of the drug, OVIs may also contaminate
the products during packaging, storage in warehouses and/or during
While solvents play a key role in the production of
pharmaceuticals, there is also a downside, as many of the
solvents used have toxic or environmentally hazardous properties.
Complete removal of residual levels of solvents is impractical from a
manufacturing standpoint, so it is inevitable that traces will remain inthe final product. The presence of these unwanted chemicals even
in small amounts may influence the efficacy, safety and stability of
the pharmaceutical products. Because residual solvents have no
therapeutic benefits but may be hazardous to human health and
the environment, it must be ensured that they are either not present
in products or are only present below recommended acceptable
levels. It is a drug manufacturer’s responsibility to ensure that any
OVIs present in the final product are not harmful to humans and
that medicinal products do not contain levels of residual solvents
higher than recommended safety limits. Solvents known to cause
unacceptable toxicity should be avoided unless their use can be
justified on the basis of a risk-benefit assessment2
. Because of their
proven or potential toxicity, the level of residual solvents is controlled
through national and international guidelines, for example, through
the FDA and International Conference on Harmonization.
“All drug substances, excipients, and products are subject to
relevant control of residual solvents, even when no test is specified
in the individual monograph.”
Regulatory and Compliance Environment
One of the essential aspects of pharmaceutical manufacturing
is regulatory compliance, which typically encompasses two aspects.
The first is compliance with private sets of standards based on
an applicant filing with a regulatory agency, which requires the
applicant to report the determined residual solvent levels in a
number of representative batches of pharmaceutical product to
establish typical levels of solvent contamination that can routinely
be achieved. Based on a statistical evaluation of the reported
data, a specification is agreed for solvents used in the final step of
the process and a decision made on whether testing is required
for solvent used at earlier stages in the process. To arrive at a
specification that is a measure of the routine performance of the
process, regulatory agencies require numerical data rather than
reporting compliance with a limit test.
Internationally, there has been a need to establish regulatory
standard guidelines. In 1997, The International Conference on
Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH), through its Q3C Expert
working group formed by regulators from the three ICH regions,
industry representatives and interested parties/observers, finalized
the Q3C guideline on residual solvents. Essentially, ICH has
consistently proposed that limits on organic solvents be set at levels
that can be justified by existing safety and toxicity data, and also kept
proposed limits within the level achievable by normal manufacturing
processes and within current analytic capabilities.
The second aspect is compliance with public standards set
by Pharmacopoeias from the three ICH regions (United States
Pharmacopoeia (USP), European Pharmacopoeia (Ph. Eur.) and
Japanese Pharmacopoeia (JP)) and also with local pharmacopoeias
from countries outside the ICH regions. In the recent past, guidelines
for organic residual solvents for public standards have generally
been vague and not up-to-date. The pharmacopoeial approach
was typically a limit test for residual solvents, employing standard
. The USP set the official limits in USP 23rd edition in the
general chapter 467, Organic Volatile Impurities5
. Very early on,
the Ph. Eur. employed the ICH Q3C regulatory approach and
updated the acceptance limits but kept the methodology as a limit
test based on standard addition. The general method in Ph. Eur. for
Identification and Control of Residual Solvents in drug substances
defines a general procedure and describes two complementary gas
chromatography (GC) conditions for identifying unknown solvents.
‘‘System A’’ is recommended for general use and is equivalent
to ‘‘Methods IV and V’’ of the USP for analysis of volatile organic
impurities ‘‘System B’’ is used to confirm identification and to solve
co-elutions. Implementation of this general method is a subject of
debate in the pharmaceutical industry due to its limited selectivity
. Historically, until its 27th edition, the USP restricted
its listing of residual solvents to those of Class 1 and neglected to
consider the wide range of organic solvents used routinely in the
pharmaceutical industry. Furthermore, the limits stated for Class 1
solvents like benzene, chloroform, 1, 4-dioxane, methylene chloride,
and 1, 1, 1-trichloroethane are in the range 2–600 (ppm) and are
therefore not in concordance with the ICH guideline. Residual
solvent testing using GC has been included in the pharmacopeias
for almost 20 years, while residual solvent-test methods have
been reported in the literature since before that. With USP 28, the
public standard for residual solvents was updated to comply with
the ICH Q3C guideline, but the methodology (the same limit-test
approach as Ph. Eur.) and the targeted monographs were not
considered appropriate by industry and regulators, leading to a
notice postponing implementation in USP 296
The objective of this guidance is to recommend acceptable
amounts for residual solvents in pharmaceuticals for the safety of
the patient. The guidance recommends use of less toxic solvents
and describes levels considered to be toxicologically acceptable
for some residual solvents.
Residual solvents in pharmaceuticals are defined here as
‘organic volatile chemicals that are used or produced in the
manufacture of drug substances or excipients, or in the preparation
of drug products’. This guidance does not address solvents
deliberately used as excipients nor does it address solvates.
However, the content of solvents in such products should be
evaluated and justified.
Since there is no therapeutic benefit from residual solvents,
all residual solvents should be removed to the extent possible to
meet product specifications, good manufacturing practices, or other
quality-based requirements. Drug products should contain no higher
levels of residual solvents than can be supported by safety data.
Some solvents that are known to cause unacceptable toxicities
(Class 1) should be avoided in the production of drug substances,
excipients, or drug products unless their use can be strongly justified
in a risk-benefit assessment. Some solvents associated with less
severe toxicity (Class 2) should be limited in order to protect patients
from potential adverse effects. Ideally, less toxic solvents (Class 3)
should be used where practical7
Scope of the Guidance
Residual solvents in drug substances, excipients, and drug
products are within the scope of this guidance. Therefore, testing
should be performed for residual solvents when production or
purification processes are known to result in the presence of such
solvents. It is only necessary to test for solvents that are used or
produced in the manufacture or purification of drug substances,
excipients, or drug products. Although manufacturers may choose
to test the drug product, a cumulative method may be used to
calculate the residual solvent levels in the drug product from the
levels in the ingredients used to produce the drug product. If the
calculation results in a level equal to or below that recommended
in this guidance, no testing of the drug product for residual solvents
need be considered. If, however, the calculated level is above the
recommended level, the drug product should be tested to ascertain
whether the formulation process has reduced the relevant solvent
level to within the acceptable amount. Drug product should also be
tested if a solvent is used during its manufacture.
This guidance does not apply to potential new drug substances,
excipients, or drug products used during the clinical research
stages of development, nor does it apply to existing marketed
drug products. The guidance applies to all dosage forms androutes of administration. Higher levels of residual solvents may be
acceptable in certain cases such as short-term (30 days or less)
or topical application. Justification for these levels should be made
on a case-by-case basis7
Classification of Residual Solvents
OVIs are classified into three classes on the basis of their
toxicity level and the degree to which they can be considered
an environmental hazard. The list provided in the guideline is
not exhaustive, and one should evaluate the synthesis and
manufacturing processes for all possible residual solvents.
The term, tolerable daily intake (TDI), is used by the International
Program on Chemical Safety (IPCS) to describe exposure limits
of toxic chemicals and the term, acceptable daily intake (ADI), is
used by the World Health Organization (WHO) and other national
and international health authorities and institutes. The new term,
permitted daily exposure (PDE), is defined in the present guidance
as a pharmaceutically acceptable intake of residual solvents to avoid
confusion of differing values for ADI’s of the same substance7
Residual solvents are classified on the basis
of risk assessment:
1. Class 1 solvents (Solvents to be avoided): Known human
carcinogens, strongly suspected human carcinogens, and
2. Class 2 solvents (Solvents to be limited): Non-genotoxic
animal carcinogens or possible causative agents of other
irreversible toxicity such as neurotoxicity or teratogenicity.3. Class 3 solvents (Solvents with low toxic potential): Solvents
with low toxic potential to man; no health-based exposure limit
is needed. Class 3 solvents have PDE’s of 50 milligrams (mg)
or more per day.
4. Class 4 solvents (Solvents for which no adequate
toxicological data was found): No adequate toxicological
data on which to base a PDE (permitted dose exposure) was
Environmental Regulation of Organic Volatile
Several of the residual solvents frequently used in the
production of pharmaceuticals are listed as toxic chemicals in
Environmental Health Criteria (EHC) monographs and in the
Integrated Risk Information System (IRIS). The objectives of such
groups as the International Programme on Chemical Safety (IPCS),
the U.S. Environmental Protection Agency (EPA), and the U.S.
Food and Drug Administration (FDA) include the determination
of acceptable exposure levels. The goal is protection of human
health and maintenance of environmental integrity against the
possible deleterious effects of chemicals resulting from long-term
environmental exposure. The methods involved in the estimation
of maximum safe exposure limits are usually based on long-term
studies. When long-term study data are unavailable, shorter term
study data can be used with modification of the approach such as
use of larger safety factors. The approach described therein relates
primarily to long-term or lifetime exposure of the general population
in the ambient environment (i.e., ambient air, food, drinking water,
and other media) 7
Limits of Residual Solvents
Solvents to Be Avoided: Solvents in Class 1 (Table 1) should
not be employed in the manufacture of drug substances, excipients,and drug products because of their unacceptable toxicity or their
deleterious environmental effect. However, if their use is unavoidable
in order to produce a drug product with a significant therapeutic
advance, then their levels should be restricted as shown in Table
1, unless otherwise justified. The solvent 1, 1, 1-Trichloroethane
is included in Table 1 because it is an environmental hazard. The
stated limit of 1,500 ppm is based on a review of the safety data
Analysis of Residual Solvent in
The analysis of residual solvents is an essential part in the
quality control of drug substances used in preclinical or clinical
trials as well as for use in commercial drug products. Residual
solvent analysis of bulk drug substance and finished pharmaceutical
products is necessary for a number of reasons such as –
1. High levels of residual organic solvents represent a risk to human
health because of their toxicity.
2. Residual organic solvents also play a role in the physicochemical
properties of the bulk drug substance. Crystalline nature of the
bulk drug substance can be affected. Differences in the crystal
structure of the bulk drug may lead to changes in dissolution
properties and problems with formulation of the finished
3. Finally, residual organic solvents can create odor problems
and color changes in the finished product and, thus, can lead
to consumer complaints.
4. Often, the main purpose for residual solvent testing is in its use
as a monitoring check for further drying of bulk pharmaceuticals
or as a final check of a finished product.
5. Testing for solvent content in intermediates may need to be
performed if a critical amount of residual solvent(s) remaining
in the intermediate can alter the next step of the process.
6. Knowledge of the solvent content in the starting materials may
help to the development chemist to understand the synthetic
routes and predict potential process related impurities.
7. Knowing the solvents used in the process allows the development
chemist to look for possible compound- solvent interactions
which can lead to the formation of impurities5, 16
Residual solvent analysis can be performed with a large array of
analytical techniques17. The most popular, and the most appropriate,
specific solvent analysis is testing by gas chromatography (GC).
Modern capillary-column gas chromatographs can separate a large
number of volatile components, permitting identification through
retention characteristics and detection at ppm levels using a broad
range of detectors5
.Gas chromatographic testing can be categorized
into three main procedures according to the means of introducing
the sample into the instrument. A direct gas chromatographic
procedure is one in which a portion of the actual drug substance
or formulation is injected into a GC system. The drug substance
is usually dissolved in an appropriate solvent and loaded into a
syringe and injected. Headspace analysis, on the other hand, is
an indirect testing procedure. The analysis is conducted when a
volume of gas above the drug substance or formulation is collected
and analyzed by a gas chromatograph. Finally, solid-phase microextraction (SPME) is making much progress in recent years for
residual solvent testing. In SPME, a silica fiber coated with a sorbent
is used to collect and concentrate the volatile solvents. The volatiles
are then thermally desorbed in the inlet of the gas chromatograph
Many alternatives to gas chromatography have been used to
determine the level of residual solvent in pharmaceutical products.
Many of these procedures are either nonspecific—that is, the
solvents are not identified—or they have high detection limits, so
they are inappropriate for the detailed product characterization
required for a regulatory submission. The oldest and simplest
method for determining the quantity of volatile residue is measuring
the weight loss of a sample during heating. LOD method is widely
used, particularly for Class 3 solvents, due to its simplicity and
ease of introduction into even the most basic analytical laboratory5
Another approach is to use thermogravimetric analysis (TGA),
which is a well-known method for the quantitative analysis of the
loss of volatile components from a sample18. Spectroscopic and
spectrometric methods have generally lacked the low detection
limits needed for toxic residual solvents, although the detection limits
would be applicable for ICH class 2 and 3 solvents. In the case of
Infrared Spectroscopy (IR), a detection limit above 100 ppm and
lack of accuracy at low concentrations of residual solvent has been
reported. For NMR also high detection limit has been reported5
Whenever organic solvents are used in the production of
pharmaceutical products, especially in the last processing steps,
the content of residual solvent in the final product should be
analyzed. The complete removal of residual level of these solvents
is impracticable and traces always remain in the final products.
The presence of these residual solvents even in small amounts
has a negative influence not only on the quality of products but
also on human health. Acceptability of residual solvents seems to
be best judged following the ICH residual solvent guideline which
is adopted by the USP, EP and JP; it classifies the solvent into
four groups. In class 1 are included the most toxic solvents which,
unless strongly justified, should be avoided. For the toxic solvents
of class 2, the limits are expressed as concentrations (ppm) and
additionally in the case of known daily drug intake, by the very
important ‘permitted daily exposure’ (PDE). The class 3 includes
the solvents with low toxic potential for which the general limit is
set at 0.5%. The class 4 includes solvents for which no adequate
toxicological data was found.
1. Michulec M., Wardenki, W.; Development of headspace solid-
phase micro-extraction-gas chromatography method for the
determination of solvent residues in edible oils and pharmaceuticals,
J. Chromatogr, 2005; 1071: 119-124.
2. Dwivedi A. M., Residual solvent analysis in pharmaceuticals.
Pharmaceutical Technology 2002; 42-46.
3. Camarasu C., Unknown residual solvents-identification in
drug products by headspace solid phase microextraction gas
chromatography and mass spectroscopy, Chromatographia 2002;
4. Rocheleau M J., Measuring residual solvents in pharmaceutical
samples using fast gas chromatography techniques, J. Chromatogr.
B 2004; 805: 77-86.
5. B’Hymer C., Residual solvent testing: A review of gas chromatographic
and alternative techniques, Pharm. Res. 2003; 20, 337-343.
6. Otero, R., Carrera, G., Static headspace gas chromatographic
method for quantitative determination of residual solvents
in pharmaceutical drug substances according to European
pharmacopoeia requirements, J. Chromatogr. A 2004; 1057: 193-
7. ICH Q3(C), Impurities: residual solvents, 1997.
8. Countrymen, S. Understanding the revision to USP monograph 467;
residual solvents, phenomenex Inc. Torrance, CA, USA, 2007.
9. General chapters 466; «Ordinary impurities» and 1086, «Impurities
in official articles,» in USP 28–NF 23. US Pharmacopoeia. 12601
Twin brook Parkway, Rockville, Maryland 20852, USA, 2004.
10. European pharmacopoeia, Identification and control of residual
solvents (2.4.24), directorate for the quality of medicines of the
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