February 2023
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in February 2023 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Reporting organic impurity content

For impurities <1.0%, report results to two decimal places (e.g. 0.06%, 0.13%).  For impurities ≥1.0%, report results to one decimal place (e.g. 1.3%). All impurities above the reporting threshold should be summed and reported as total impurities. When comparing to a reporting, identification or qualification threshold, the result should first be rounded to the same decimal place as the threshold. Thresholds have to be exceeded to apply.

 

Ph. Eur. status in Europe

As the official pharmacopoeia in the European Economic Area (complemented by national pharmacopoeias where relevant), the Ph. Eur. helps define the requirements to obtain a marketing authorisation. The quality standards it contains are legally binding. However, appropriately validated, alternative test methods (though not specifications) can be submitted for approval by competent authorities during MA application procedures.

 

Ph. Eur. status in Britain

Many people think that the Ph. Eur. is a publication of the EU. It is not! It is published by the Council of Europe, an organisation completely distinct from the EU. The United Kingdom remains a member of the Council of Europe and party to the Convention on the Elaboration of a European Pharmacopoeia irrespective of Brexit. Therefore, the Ph. Eur. remains legally binding in the UK.

 

Checking CEPs

Upon receipt of a certificate of suitability, check that it is complete i.e. all pages are present and all Annexes attached. Check the EDQM Knowledge Database to ensure that the CEP is current and valid. Before submitting the CEP to a competent authority, make sure that the Declaration of Access has been completed by the CEP holder, authorising you to use the document.

 

 

 

January 2023
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in January 2023 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Reporting impurities

ny impurities present above the reporting threshold should be reported individually. Reporting a ‘maximum observed impurity’ provides very little information on the analyte’s impurity profile, especially when trying to observe trends during stability studies. For in-house evaluation, it is preferable to individually report all impurities at or above the LOQ.

 

Dissolution profiling of biobatches

Study the dissolution profiles of your bioequivalence study batches in as many media using as many different test parameters as possible. Characterisation of biobatch dissolution will form the basis for your dissolution specifications throughout your product’s lifecycle. The more information you collect, the more thankful you’ll be years down the line.

 

Specifications in the Dossier

 

Specifications presented in a marketing authorisation application should be numbered and dated. Many assessors will insist on this, and it is good practice in any case, for traceability. It is advisable to create an SOP laying out the numbering system and linking back to in-house specifications.

 

Polymorphism

For polymorphic drug substances, you need to demonstrate that: 1. The same form of the drug substance is consistently synthesized and does not change during the retest period. 2. Conversion to a different form does not occur during finished product manufacture and shelf-life. If conversion does occur, you will have to show that product performance, safety and efficacy are not affected.

 

 

 

December 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in December 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

SOPs in the Dossier

Resist the temptation to include SOPs in an IMPD or Module 3. SOPs invariably contain excess information that is not relevant to a regulatory application. Instead, get an experienced regulatory technical writer to pare down your manufacturing and analytical procedures to the essentials for presentation in the dossier.

 

Mass Balance

Take a long, hard look at your stability results. Is any reduction in assay accompanied by a corresponding increase in degradation products? If not, you have a mass imbalance which you should investigate thoroughly. Mass imbalances are normally due to analytical deficiencies but can happen for other reasons e.g. API sublimation.

 

Reviewing an IMPD or Module 3

When preparing to submit a clinical trial or marketing authorisation application, get one experienced reviewer to read the IMPD or Module 3 from cover to cover. In our experience, he or she will uncover a surprising amount of inconsistencies that reviewers of individual sections will not catch.

 

 

November 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in November 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Updating a QOS

It is good practice to keep your Quality Overall Summary fully updated at all times, even if not strictly required by competent authorities. When done properly, the QOS focuses on the salient points of Module 3 and can be used to quickly familiarise staff, QPs and consultants with a product (as well as to refresh one’s memory!)

Compatibility

Section 3.2.P.2.6 of the CTD is only applicable if reconstitution diluents or dosage devices are required to administer the product. Information on the compatibility of the drug product with any diluents or devices (e.g. precipitation, sorption, stability) should be provided. Compatibility with excipients and the container closure system is tackled elsewhere.

Reduced testing of starting materials

Reduced or skip-lot testing of starting materials (APIs, excipients and packaging materials) is fully covered by EU GMP and is not product-specific. Therefore, in the relevant specifications in the MA application you should not include any reference at all to reduced testing on receipt by the finished product manufacturer. CMC assessors will object if you do.

Finished product assay limits

Finished product assay limits at release of ±5% are acceptable in the EU without further justification. Wider limits (even if based on pharmacopoeial monographs) have to be soundly justified based on production variability, the analytical test procedure, stability data and other relevant considerations. This differs from the North American norm, where assay limits at release are typically ±10%.

Ingredients in the eAF

When preparing to submit a European MAA, make sure that the dropdown lists in the eAF include all the ingredients your formulation contains. If not, you will need to get in touch with EMA in advance to get the ingredient included in the lists. So don’t leave it till the last minute.

Otober 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in October 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Acceptance Criteria for Microbiological Quality

Ph. Eur. and USP acceptance criteria for microbiological quality are interpreted as follows: - 101 CFU: maximum acceptable count is 20 not 10 - 102 CFU: maximum acceptable count is 200 not 100 and so on. This seems counterintuitive, but the leeway is meant to allow for the poor accuracy and precision of microbiological enumeration.

EPCRS

When a European Pharmacopoeia Chemical Reference Substance is available, European competent authorites will generally expect it to be used as the primary standard for the in-house qualification of secondary (working) standards. Other sources of primary standards are considered less authoritative in the region.

Structuring Module 3

A well-structured dossier is so much easier to evaluate. If you wish to facilitate review, list tests in the same order throughout the dossier: in the specifications table, when describing analytical procedures, when justifying specifcations, on COAs, and in the batch analyses and stability tables.

 

 

September 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in September 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

EMA Training Materials

Recordings and/or presentations from EMA workshops are generally available on the EMA website for years following the event, providing a wealth of information and training materials. Some of the CMC-relevant workshops on the website are the ones on biopharmaceuticals, development for paediatric use, ICH Q3D, and many more.

 

When is an Excipient Novel?

A novel excipient is a new or well-established chemical entity being used for the first time in a drug product or by a new route of administration. When determining if an excipient is novel or not, consider use throughout the ICH regions. European competent authorities have been known to regard excipients as non-novel when used extensively in ICH regions other than Europe.

 

IMPDs for Small Molecule Drugs

For Phase I studies, stability data on the IMP need not be available at clinical trial application stage. However, the assigned shelf-life must be justified, studies under accelerated and long-term conditions initiated before study start, and an ongoing stability program performed with the relevant batches. For Phase II and III studies, stability data at accelerated and long-term conditions must be submitted for evaluation in the IMPD.

 

Leaching and Sorption

Interaction studies identify any unacceptable effects of packaging materials and drug substance/product on each other. In Europe, interaction studies might be required for solid drug products intended for inhalation, parenteral or ophthalmic administration but not other solids. Migration studies are needed for non-solid drug substances and drug products whenever extraction studies have identified the presence of one or more extractables. Sorption studies are needed for non-solid drug products when changes observed during stability studies might be due to interaction with packaging materials

 

Dissolution Limits for Generic SODs

When selecting biobatches, bear in mind that the future dissolution specification for your product will be tied to the dissolution results for the biobatches. Typically, you will not be allowed to set a Q value that differs by >10% from the biobatch dissolution result (the mean value of 12 units dissolved in 15, 30 or 45 minutes, depending on how quickly your formulation reaches 85% dissolution). The minimum acceptable Q for a single point dissolution test is 75% at 45 minutes. Assessors will not accept justifications claiming that a specification is too tight to comply regularly with S1 because consistent compliance with S2 is perfectly acceptable.

 

 

August 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in August 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

 

Extractables

For solid oral dosage forms, biowaivers for additional strengths are possible if the qualitative composition and manufacturing process are the same, the strengths are quantitatively proportional (excluding coating components, capsule shells, colours and flavours), and supportive in vitro dissolution data are available. If the drug substance constitutes less than 5% of tablet core weight, some deviation from quantitative proportionality is permitted. Each layer of bilayer tablets is considered independently. Fixed combinations are more complicated, therefore detailed worked examples have been provided by the PKWP in Q&A 6.4.

 

 

 

 

 

July 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in July 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

Cross-Checking of Formulae

Inconsistencies between unit formulae in 3.2.P.1 and manufacturing formulae in 3.2.P.3.2 are very common. Make sure that the quantities in the formulae can easily be converted into each other by multiplying or dividing by the number of dosage units in the batch. To minimise the effect of rounding, derive the unit formula from the batch formula and not the other way round, and choose an appropriate number of decimal places. Also check the total weights or volumes - do the quantities in your composition tables add up to the stated totals? Have density, overfills and overages been taken into consideration and clearly stated?  

Secondary & Tertiary Packaging

Module 3.2.P.7 of the dossier should focus on primary packaging - the packaging that comes into direct contact with the product. Secondary packaging should only be described briefly, unless it is functional (providing additional protection or serving to deliver the product). If functional, additional relevant information should be provided, such as a specification. No information on tertiary packaging should be presented.

Drug Substance Specifications

The applicant's specification for a drug substance presented in the MA dossier should match that of the ASMF or CEP holder, unless certain tests can justifiably be omitted e.g. superfluous tests or limits that are too tight. The applicant's specification may include additional tests, if critical to the quality of the drug product e.g. bacterial endotoxins. If there is more than one drug substance supplier, the applicant's specification for the substance should consolidate the various sets of specifications.

Biowaivers for SODs

For solid oral dosage forms, biowaivers for additional strengths are possible if the qualitative composition and manufacturing process are the same, the strengths are quantitatively proportional (excluding coating components, capsule shells, colours and flavours), and supportive in vitro dissolution data are available. If the drug substance constitutes less than 5% of tablet core weight, some deviation from quantitative proportionality is permitted. Each layer of bilayer tablets is considered independently. Fixed combinations are more complicated, therefore detailed worked examples have been provided by the PKWP in Q&A 6.4.

 

 

June 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in June 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

The EDQM Knowledge Database 

The free Knowledge Database on the EDQM website is an extremely useful resource. From it you can find out monograph status: if a monograph is available, under elaboration, being revised, harmonised, and interchangeable. The monograph’s revision history tells you what changes happened and when. Certificates of suitability granted for the substance are listed. In many cases, the database also provides specimen chromatograms and lists reference standards (with links to the EDQM reference substances database), chromatography columns and key reagents required for testing.

Revision of Nitrosamine Risk Assessments

ou have performed a nitrosamine risk evaluation for your small molecule product and have submitted a ‘No risk identified’ notification to EMA or national competent authorities. However, nitrosamine risk evaluation must continue throughout your product’s lifecycle. Monitor newly identified root causes published by EMA and elsewhere. Consider the potential risk of nitrosamine formation as part of your change control process. Perform periodic re-evaluation

ICH Training Materials

Everyone in the industry is familiar with ICH guidelines, which provide harmonised guidance on various technical matters. On the other hand, most users of the guidelines are unaware of the extensive training materials that accompany many of the guidelines and are available for free on the ich.org website in the form of presentations, supporting documents and videos. As an example, ICH Q9 on Quality Risk Management is supported by a briefing pack with presentations on the various risk management methods and tools.

Related Substances Specifications

Thresholds for setting impurity limits in finished product specifications are calculated with reference to the maximum daily dose (MDD) of the drug. The MDD is the maximum approved daily dose in the target countries for the drug substance via the route of administration of interest. (The approach is different for fixed dose combination products, for which thresholds are based on the MDD in the SmPC for the product under evaluation.) The calculated thresholds are the same for all strengths of a product.

Unidentified Impurities in Fixed Dose Combination Products

In fixed dose combination products, it may be difficult to associate unidentified related substances with a particular drug substance. This becomes more complicated when identification thresholds differ for the drug substances in the combination. In that case, specifications for unidentified impurities must be based on the lowest threshold for the drugs in the combination. When the threshold is exceeded, the impurity should be identified and associated with the correct drug substance.

 

 

 

May 2022
Real CMC Tips and Insights

Since the beginning of July 2020, we have published weekly Regulatory tips and insights from our Regulatory experts on our Real Regulatory LinkedIn page, as a service to our followers. The tips we published in May 2022 are collected here, for convenience. Make sure you follow  Real Regulatory Ltd and Real CMC for regulatory news, reports and hints.

EudraGMDP & MHRA-GMDP

EudraGMDP (eudragmdp.ema.europa.eu) is a very useful public database of pharmaceutical manufacturers, importers, and wholesale dealers, which can be used to verify GMP/GDP status but also (through the MIA/GMP Operations Search and the API Search) to identify sites approved to perform activities of interest. Historical data on UK sites remains in the database even now that the Brexit transition period has ended, but for more up-to-date information use the UK database with similar functionality: MHRA-GMDP (cms.mhra.gov.uk/mhra).

ASMF Version Discrepancies

An ASMF may be submitted by an ASMF holder to support multiple MA or variation applications made by different applicants for different products. Each update to an ASMF, whether required during assessment or initiated by the ASMF holder, results in an updated ASMF version number. Discrepancies in version numbers are among the commonest validation issues, therefore it is crucial to confirm with the ASMF holder - before submitting - that the applicant’s part is the most recent available version and matches the restricted part submitted by the ASMF holder.

The Applicant’s Drug Substance Module

When an ASMF is used to submit information on a drug substance to competent authorities, the applicant must still present a drug substance module as follows: the applicant’s specifications and analytical procedures for the material in 3.2.S.4.1 and 3.2.S.4.2, analytical validation in 3.2.S.4.3 (if the applicant’s analytical procedures are not identical to those validated by the ASMF holder), batch analyses in 3.2.S.4.4, justification of specifications in 3.2.S.4.5 and information about reference standards in 3.2.S.5.

 

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