The Odd Couple – Part 2: Authoring the Manufacture of Drug Substance and Drug Product Modules (S2, P3)

This full Series follows our initial Primer blogs: Constructing the CTD Quality Module 3, and Quality Overall Summary: Reviewers Guide. For the purposes of this blog series, it will be necessary to produce an admittedly unbalanced summary that shortchanges some sections of the Quality Module but that includes considerable discussion of other sections that can largely influence the ultimate success or failure of an application. I have therefore focused discussion on selected aspects from a remarkably diverse and technical exercise, which is the production of the CTD Quality Module.

• Part 1 covered authoring the General Information and Characterization of the Drug Substance Modules;
• Below in Part 2 we cover Authoring for the Manufacture of Drug Substance and the Drug Product;
• Part 3 will cover the Control of Excipients;
• Part 4 will cover the Control and Analysis of Substance and Product;
• Part 5 will cover the Packaging and Labeling submission content;
• Parts 6 Stability of Drug Substance and Drug Product;
• Part 7 will conclude with the Composition and Pharmaceutical Development Modules

The CTD Module 3

Though the content of these modules is generally well defined, according to the various guidance documents previously referred to, considerable latitude for assimilating, discussing, comparing, and contrasting data is allowed and even encouraged. There are opportunities to be creative, to tell a story, and to craft cohesive arguments to help regulatory bodies understand your product.  

CTD Module 3 is well defined containing both drug substance (active ingredient) and drug product sections, with each containing required presentations of drug technical information, processes and key parameters, and various justification supported by qualification and validation studies.

This data and these reports provide the detailed evidence that a drug’s characteristics are well defined and well controlled, such that one can assure that the next lot produced is essentially the same as the last lot. Drug manufacture control and reproducibility is the essential message that Module 3 must convey if Agency reviewers are to conclude that a new drug application merits approval.

Sponsors have latitude in how data are presented, and how important messages are formatted in the compilation of a CTD application.

Preparation of CTD submissions for various regulatory authorities should be geared toward meeting those unique regulatory standards.

DRUG SUBSTANCE MANUFACTURE

S.2.1. Manufacturer(s)

The name, location, and current Good Manufacturing Practice (cGMP) status of the manufacturer of key starting materials and drug substance should be provided.

An overview of the quality assurance aspects of the manufacturers may provide insight into the viability of the process. Although not required to be included in the application, a request for the report of the most recent cGMP manufacturing inspection from the US Food and Drug Administration (FDA) and/or European Union (EU) agencies enable a broad overview of the cGMP compliance aspects of the facilities.

Specific indications of issues concerning testing practices or general cGMP compliance may help determine the reliability of the various data supplied by the manufacturer. If testing is performed at another facility, an investigation as to the cGMP status of the testing facility should be pursued.

An inventory of available drug substance (suitable for clinical supplies) and critical raw materials should be available. A review of supply agreements and contractual obligations for critical raw materials should be performed to assure the availability of future supplies. In addition, alternate suppliers for critical materials should be identified and qualified.

S.2.2. Description of Manufacturing Process

A process flow diagram and flowchart summary of the process should be provided with the molecular formulas, reactant quantities, yields, operating conditions, solvents, and Critical Quality Attributes (CQA’s).

A detailed narrative description of each step in the manufacturing process is typically available from early phase regulatory documents. This narrative should be compared with actual batch records from the manufacturing facility.

A detailed analysis of the manufacturing process should include a review of quantities of raw materials, solvents, catalysts, reagents, identification of critical steps and process controls, the type and size of processing equipment, and operating conditions, such as temperature, pressure, pH, and mixing time.

If the process has been scaled-up from earlier batches used in toxicological studies, the impurity profile should be compared with the earlier toxicology study batches. A review of the raw materials should include the availability of reagents and safety concerns.

Some questions that should be addressed in the submission where necessary or that should be discussed if questions are anticipated during review include:

1. What is the robustness of the process (are re-works common)? How do the physicochemical profiles of multiple lots compare?
2. Have critical quality attributes for critical intermediates and final drug substance been determined?
3. Have Critical Processing Parameters (CPPs) been associated with critical quality attributes (are there data to support the association)?
4. Has the commercial synthesis been defined? Can the process batch size be increased using the current synthesis?
5. Have suitable process hold points been determined? What is the impact on quality/stability of drug substance?
6. Are the crystallization procedures well defined and what is the risk of polymorph formation considering the results of polymorph screening studies?
7. Are micronization techniques employed? Does the micronization impact the quality (e.g. formation of degradation products or amorphous material from crystalline solids) of the final drug substance?
8. Are any of the reagents of animal origin? If so, is their Transmissible Spongiform Encephalopathy (TSE) status documented

Some questions that should be discussed internally, to contain costs or if change control is anticipated during or post-approval include:

1. Are the reagents commonly available?
2. Is the batch yield consistent and reproducible? This analysis will entail reviews with marketing to determine the acceptable cost of goods for the drug substance.
3. Is the cycle time for processing of the drug substance acceptable?
4. Are there any environmental or safety concerns?
5. Is the current synthesis amenable to manufacturing capabilities at existing plants? Are the technologies used in the process common; is special equipment required?

S.2.3. Control of Materials

A discussion of the controls selected for each reagent should indicate the rationale for acceptance criteria regarding the quality impact on the drug substance. The acceptance criteria and test methods for the starting materials, solvents, reagents, catalysts, and any other materials used in the manufacture of the drug substance should be evaluated.

The acceptance criteria for starting materials should consider those qualities critical to the operation. For instance, the moisture content of a reagent may impact the formation of side-products.

Regulatory Starting Material

According to ICH Q7, a Regulatory Starting Material is defined as the point at which the sponsor commits to GMP manufacture of a drug substance. Drug substance processes are generally convergent, and each branch of the synthesis begins with one (or more) starting materials.

To protect patients from potential unknown impurities introduced prior to the GMP process, proposing noticeably short synthetic routes with complex custom-made starting materials without an appropriate control strategy is not recommended; and, guidance is provided in ICHQ11.

While the ICHQ11 guidance has been in place for several years inconsistent application of ICHQ11 principles still lead to discussions between sponsors and regulators. Health authorities have challenged starting material designation for Phase III and market applications and are now starting to ask significant questions even for earlier phases of development.

S.2.4. Control of Critical Steps and Intermediates

Description of Analytical Methods

The analytical methods used to control starting materials, reagents, and drug substance should be reviewed. Sufficient detail should be provided in any application so that the methods could be run in the laboratory. For example, HPLC methods should provide detail on the type of column used, run time, mobile phase composition, flowrate, and detection means.

Adequate validation data should be available to assure the accuracy of the data used to support the physio-chemical properties of the drug substance.

The ICH text on the validation of analytical procedures provides a good overview of the type of information that should be included in the validation package. Key items include accuracy, linearity, precision (repeatability and intermediate precision), robustness, and specificity.

While all these aspects of validation may not be complete in early phases of development, they should be available at the time of submission to assure the accuracy of the information provided. In particular, the limit of quantitation should be at least 0.05% to provide adequate representation of the impurity profile.

Some compounds may have isomeric forms which can be characterized as structural (e.g., cis/trans isomers) or stereoisomers (e.g., enantiomers). Control of structural isomers is routinely accomplished by reversed phase HPLC.

Compounds with molecular dissymmetry must have control methods that determine the enantiomeric purity (typically expressed as enantiomeric excess). These separations are performed using chiral stationary phases (direct technique) or derivatization of the molecule to form diastereomers (indirect method) which may in turn be separated on achiral stationary phases.

Since isomers may have different toxicological and pharmacological profiles, adequate control methods must demonstrate the purity of the drug substances. A good overview of the use chiroptical spectroscopy in the characterization of pharmaceutical compounds can be found in the Literature.

Solvents and Reagents

In reviewing the batch records of the lots of drug substance produced, the certificate of analysis for each solvent and reagent used should be compared with any critical attributes identified in the process discussion.

Certain solvents rarely used in full-scale operations should be avoided as the process moves from the pilot to commercial scale. These include the solvents pentane, hexane, benzene, chloroform, carbon tetrachloride, 1,4,-dioxane, and several ethers whose risks include safety and environmental issues.

Catalyst

If part of the process, a residual catalyst test should be performed at the end of each process step where a catalyst is used. If these results are not available, a test should be performed for the drug substance. The levels of metallic catalysts are the subject of regulatory scrutiny and the limits should be based upon process capability and safety considerations.

The European Agency for the Evaluation of Medicinal Products provides specific guidance on the limits of residual metal catalysts. Typically, a heavy metals test is conducted for the drug substance.

Quality Control of Critical Manufacturing Steps

cGMP controls should be applied to all manufacturing steps beginning with the regulatory starting materials. Adequate process control is achieved when there is an understanding of each process step and its associated critical quality attributes. Critical Quality Attributes (CQA) are applied to those process steps that have an impact on the final quality of the drug substance. For each reaction step, the impact on the final drug substance should be determined. Some questions to be addressed are:

1. What process impurities are generated?
2. What process parameters influence the level of the process impurity?
3. How are the process parameters that influence product quality controlled?
4. Is the process control test reproducible?
5. Is there a clear correlation between the process control and the critical quality attribute?
6. Are the CQA results among batches consistent?

Control of Intermediates

The requirements that apply to each CQA during the synthesis should be detailed. A review of the results for several batches will give an indication of the process robustness.

The analytical methods to control the CQAs should be given including any available validation data.

S.2.5. Process Validation

Process validation is defined by ICH as the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.

The approaches to validation of bulk drug substance are outlined in the ICH document as well as other regulatory guidance documents. Some of the key aspects of validation are:

1. A validation master plan or protocol with objectives, scope, and responsibilities outlined
2. Critical process parameters (key process variables) and their associated critical quality attributes must be identified
3. Documentation of key process data during validation
4. Acceptance criteria for key process intermediates and final drug substance
5. Three consecutive successful production batches
6. Reproducibility of the impurity profile
7. Investigation of any atypical events or results occurring during validation runs

S.2.6. Manufacturing Process Development

A review of the manufacturing process development should include an emphasis on the reproducibility of the impurity profile of the drug substance. Changes to the route of synthesis during development may lead to the formation of new impurities. The review should focus on any process changes made after the first toxicology study.

All impurities must be qualified when they reach the ICH qualification threshold. For a maximum daily dose of less than or equal to 2grams/day, the qualification threshold is 0.15% or 1.0 mg per day intake (whichever is lower).

For a maximum daily dose of greater than to 2 grams/day, the qualification threshold is 0.05%. Qualification of impurities typically entails 28-day daily dosing study in mice.

Genotoxic Impurities

In addition, a package of genotoxicity assays is recommended including the bacterial mutation (Ames) test, the mouse lymphoma assay, and the rodent micronucleus test.

DRUG PRODUCT MANUFACTURE

P.3.1. Manufacturer

The manufacturer and location of the drug product facility should be identified. An overview of the quality assurance aspects of the manufacturer may provide insight into the viability of the process. The Sponsor should obtain a copy of the most recent cGMP manufacturing inspection issued by the FDA or the EU.

The Sponsor also should request copies of internal cGMP inspections. The regulatory and internal inspection reports provide a broad overview of the cGMP compliance aspects of the facility. Specific indications of issues concerning testing practices or other general cGMP compliance aspects will help to determine the reliability of the various data sets supplied by the manufacturer. If testing is performed at another facility, an investigation of the cGMP status of the testing facility is pursued.

An inventory of available drug products (suitable for commercial supplies) and critical components should be obtained. A review of supply agreements and contractual obligations for critical excipients should be reviewed to assure the availability of supplies. Alternate suppliers for critical materials should be identified.

P.3.2 Batch Formula

A batch formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards.

P.3.3. Description of Manufacturing Process and Process Controls

A flowchart summary of the process should be provided with the approximate yields, operating conditions, and critical quality attributes for each intermediate indicated. The flowchart allows for an overview of the process and an outline for ease of discussion of the various steps.

A detailed narrative description of each step in the manufacturing process typically is available from early phase regulatory documents. This narrative should be compared with actual batch records from the manufacturing facility to assess the manufacturer’s regulatory compliance.

A detailed analysis of the manufacturing process should include a review of the quantities of excipients and reagents used, the identification of critical steps and process controls, the type and size of processing equipment used, and the operating conditions, such as temperature, pressure, pH, and mixing time.

A review of the materials used in the manufacturing process should include availability and any safety concerns (the need for special processing equipment and protective gear for the operator). Some questions that should be asked include:

1. What is the robustness of the process (are reworks common, and is the rework procedure well defined)? How do the physicochemical profiles of multiple lots compare? Are the characteristics of the reworked drug product consistent with historical data for the product?
2. Have critical quality attributes for critical intermediates and final drug product been determined?
3. Have critical processing parameters been clearly associated with critical quality attributes (are there data to support the association)?
4. Are there any environmental or safety concerns?
5. Have suitable process hold points been determined? What is the impact of holding intermediates on the quality/stability of drug product? Have bulk hold studies of intermediates been performed?
6. Are any of the excipients of animal origin? If so, is their transmissible spongiform encephalopathy (TSE) status documented?

Some questions that should be discussed internally, to contain costs or if change control is anticipated during or post-approval include:

1. If the current process is at scale, can the batch size be increased by using the current manufacturing technology (has a commercial manufacturing process been defined)?
2. Is the batch yield acceptable relative to cost? This analysis will entail reviews with the business group to determine the acceptable cost of goods for the drug product.
3. Is the current manufacturing process amenable to manufacturing capabilities at existing plants? Are the technologies used in the process common; is special equipment required?
4. Is the cycle time for processing of the drug product acceptable?
5. Are any of the manufacturing steps patent protected?

P.3.4. Controls of Critical Steps and Intermediates

Critical Steps

Tests and acceptance criteria should be provided (with justification, including experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to ensure that the process is controlled.

Intermediates

Information on the quality and control of intermediates isolated during the process should be provided. Reference ICH Guidelines: Q2A, Q2B, Q6A, and Q6B

A flowchart summary of the process should be provided with the approximate yields, operating conditions, and critical quality attributes for each intermediate indicated. The flowchart allows for an overview of the process and an outline for ease of discussion of the various steps.

P.3.5. Process Validation

Process validation is defined by the International Conference on Harmonization (ICH) as the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a product meeting its predetermined specifications and quality attributes.

The approaches to validation of a drug product are outlined in several regulatory guidance documents.  Some of the key aspects of validation are:

1. Availability of a validation master plan or protocol with objectives, scope, and responsibilities outlined.
2. Critical process parameters (key process variables) and their associated critical quality attributes identified.
3. Key process data documented during validation.
4. Acceptance criteria assigned for key process intermediates and final drug product.
5. Three consecutive successful production batches produced.
6. Reproducibility of the physicochemical profile of the drug product.
7. Investigation of any atypical events or results occurring during validation runs.

“Three Critical Aspects (or Features) of the Common Technical Document (Location, Location, Location.”

Efforts over the past 20 years by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) have resulted in a unified dossier for drug applications, the Common Technical Document (CTD) for the Registration of Pharmaceuticals for Human Use. Several ICH documents related to the preparation of various Quality Module sections of the CTD were issued since 2002.

The technical information submitted in Module 2.3 and Module3 of the CTD, and the organization of the information, is carefully specified in guidance documents. Although the CTD is now the preferred format for a new drug application within the regions covered by the ICH, including the United States, the CTD does not in any way replace or supersede the regulations described for example in the US Code of Federal Regulations.

The CTD is an agreed-upon format for the presentation of summaries, reports, and data. Indeed, the actual content of the CTD must still conform to requirements and recommendations found in the regulations and in Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidance documents. Likewise, there may be components that are required by other ICH regions. 

Ultimately, the timeliness of an Agency’s review and approval status of a drug’s Quality section is best served by preparation of a well-designed Quality Module. Insights and recommendations from the past fifteen years are provided here to help maximize the potential for a successful outcome.

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