As the number of generic drug applications continues to rise each year, and the backlog of unreviewed drugs increases, FDA has taken a number of steps to improve and modernize the generic drug review process. The most significant has been establishing question-based review (QBR), a template for submitting the information required in amended new drug applications (ANDA’s).

The QBR format came about in response to long delays in approving ANDAs. Most generics companies were submitting the information required, but each was presenting data differently. For example, some companies presented information in a narrative paragraph format, while others showed the same data in tables. These inconsistencies increased review time.

In addition to improving consistency and speeding up review, QbD also aims to push generics manufacturers to develop a deeper understanding of the processes behind their drugs.  A simple “trust me” will not suffice, at any step of the product’s lifecycle.

This trend toward asking more probing questions of manufacturers, began decades ago with name-brand drugs. It has become commonplace for regulatory authorities to request developer’s notebooks to see, for example, why a specific solvent system was chosen for API synthesis, to prove that that solvents and by-products were absent from the final product, and that degradation products (on stability testing) were not carcinogenic or mutagenic.

Now under QbR, generic and contract manufacturers are being forced to go beyond the typical excuses, such as ‘I was simply using the compendial method’ or ‘I only needed the Certificate of Analysis.’  Just as the old war tribunals rejected the ‘I was only following orders’ defense, FDA and other regulatory bodies will no longer accept “plausible deniability.” All players in the game need to know and, more to the point, prove that there are no hazards from the synthesis of the API through the lot completing its stability program.

While many companies are never going to move beyond contract manufacturing in a continuous manner, some CMO’s cross the boundaries of contract manufacturing to make their own products. An example is AAI Pharma (Wilmington, NC), which started as a contract lab (originally performing stability studies). After becoming equipped to make “Brand X” for clinical trials against name-brand products for clients, it began selling the “Brand X” it formulated as its own product. The company later went on to develop its own products, moving from a contract lab to innovator. Thus, any contract company should be expected to be conversant with the ANDA submission rules and how they may be called upon to contribute to its contents.

Let’s examine the various pieces of the QbR questionnaire.

2.3.S.1 General Information
What are the nomenclature, molecular structure, molecular formula, and molecular weight? This is straightforward and, especially for a small molecule, simple to comply with. The drug has usually been around for a while and the details can almost be gotten off a website.

2.3.S.2 Manufacture
Who manufactures the drug substance? This will apply to all sources, both domestic and foreign. At this point, simply listing the actual and potential suppliers will suffice, but if sources change, more information will be needed.

List each participant and facility involved in drug substance manufacturing/testing activities and clearly state their function.

This is a new concept for many companies, contract of innovators. However, it has been shown that different synthesis routes can lead to different impurities and, potentially, different breakdown products under stability testing conditions. If a contract manufacturer is responsible for sourcing its own API supplier(s), it will no longer be good enough to 1) say “we accept the C of A” or, worse yet, 2) “all APIs are the same, so why worry?”

2.3.S.3 Characterization
What are the potential impurities of the drug substance? This information changes for any variance in the manufacture of the API by each supplier. They will need to be required (and watched) to inform the manufacturer is and when they change the process or, to be safe, their supplier of raw materials, as that could also affect the finished product’s purity.

For each impurity, what is the structure, IUPAC name, and origin (process or degradation)? This is also self-explanatory. It merely requires careful bookkeeping (one of the few words with three sets or letter pairs in a row) and some care in data retrieval.

2.3.S.4 Control of Drug Substance
What is the drug substance specification? At some point, the manufacturer will have to explain why a parameter such as particle size is or is not specified and how it is measured. In other words, if you have or do not have a specification for a parameter, be prepared to defend why or why not. And be prepared to show data to support your position.

For each test in the specification, what is the justification for the acceptance criterion? And, from past experience, “we’ve always done it that way” is not an acceptable criterion.

For each test in the specification, provide a summary of the analytical method(s) and, if applicable, a summary of the validation or verification report(s).

Yes, you could simply adopt the methods used by the innovator, but be prepared to defend them to the Agency.

2.3.S.5 Reference Standards
How were the drug substance and impurity reference standards certified or qualified? Pretty obvious question, but, if you refer to C of A’s, you had better show a “vendor validation report” to the inspector.

2.3.S.6 Container Closure
What container closure system is used for packaging the drug substance? Not a trivial question. I started my career >40 years ago by testing the compatibility between a dosage form and its package (plastic bottles were just beginning to be introduced and blister packs were about to “happen”). Changing a plastics supplier or source is not a trivial change. There needs to be documentation and proof that chemicals, used as antioxidants or plasticizers, are not harmful to the patient and that they do not cause chemical of physical harm to the product, itself. Any changes in plastic closure or liner need to be disclosed by the container supplier. 

2.3.S.7 Stability
What are the storage conditions and the retest/expiry period for the drug substance? Be prepared to explain why or why not a condition is or is not used and why and how you retest…along with criteria and data. For an example of conditions chosen, an API (e.g., a natural product or vaccine) that is heat labile need not be stored at elevated temperatures, especially if the storage conditions on the label state “refrigerate.” Also, tablets sold in high humidity/high temperature countries need to be tested in their final packages, not bulk, for instance.

2.3.P.1 Description and Composition
What are the components and composition of the final drug product on both a per-unit dose and %w/w basis? Obvious and relatively simple to answer; this is from the MMF (master manufacturing formula) and packaging specs.

What is(are) the function(s) of each excipient? This may not be as obvious a question to answer. If you are simply following the innovator’s formula, it may well be enough to state that fact and have the inspector refer to the original ANDA, submitted by the product’s owner.

Does any excipient exceed the FDA inactive ingredient database limit for this route of administration calculated based on maximum daily dose? If so, please justify. This information will need to be provided by whoever developed the dosage form.
What are the differences between this formulation and the Reference Listed Drug (RLD) formulation? Also pretty obvious, although, if there are large differences, be prepared to defend them.

2.3.P.2 Pharmaceutical Development
What are the characteristics of the RLD Product? Again, this is where the physical/chemical/biological properties are outlined, usually by the innovator company. These may include the label claims and package insert information (possible foods that interfere, etc.)

What are the elements, targets, and justifications of the Quality Target Product Profile (QTPP)? Again, these justifications will come from whoever formulated the product. It is meant to justify the process parameters like dissolution profile, hardness, etc.

For each quality attribute of the drug product, what is the target and how is it justified? See the last two questions.

How were the critical quality attributes (CQAs) selected? This is an innovator-based question.

If applicable, what in vitro bioperformance evaluations (i.e., dissolution method, flux assay, etc.) were used during pharmaceutical development and how were they developed? Not applicable to a contract site, unless the contract manufacturer makes changes or was the site where clinical trials were initiated.

2.3.P.2.1.1 Drug Substance
What are the physical, chemical, biological and, if applicable, mechanical properties including: physical description, pKa, chirality, polymorphism, aqueous solubility (as a function of pH), hygroscopicity, melting point(s), and partition coefficient and, when available, BCS classification? All this information should be available from the innovator company, should anyone ask.

What drug substance attributes are potentially high risk with regard to developing the drug product? Ditto: an innovator question.

2.3.P.2.1.2 Excipients
What evidence supports compatibility between the excipients and the drug substance? This would be from the pre-formulation studies, performed by the innovator company.

2.3.P.2.2 Drug Product
How were the excipient types and grades selected? Formulations team that developed the dosage form can answer this.
What aspects of the formulation were identified as potentially high risk?  Same answer as above.

2.3.P.2.2 Drug Product
What formulation development studies, including screening, characterization, optimization, and verification (robustness) if any, were conducted?

This question is self-explanatory and should be addressed by the people who handle formulation studies.

What attributes of the drug substance, excipients and in-process materials were identified as critical and how do they impact the drug product CQAs?

Again, this is obtained from whoever formulated the product.

How have the risks associated with the formulation variables been reduced to an acceptable level?

Same answer as above.

2.3.P.2.3 Manufacturing Process Development
What is the rationale for selecting this manufacturing process for the drug product?

This will become important if and when modern manufacturing techniques are introduced at contract sites. (If allowed by the product owner) the company that modernizes and uses, for example, in-line process controls will gain a competitive edge over other “conventional” manufacturers. At the point that you choose process analytical technology (PAT)-type instruments to be employed, you will need to justify/verify/validate these procedures to the Agency as well as the company with whom you are contracted.

What is the process map listing input material attributes, process parameters, and output material quality attributes for all of the unit operations in the manufacturing process? These are addressed in your Design Space plan under the PAT regimen. When the time comes, there are many sources for more information.

What is the potential risk of each process step to impact the drug product CQAs (Critical Quality Attributes) and what are the justifications? This is addressed by the innovator or, if there are process changes, the CMO.

For each potentially high risk process step: All of these will need to be documented and validated to satisfy the Agency, if and when your facility goes its own way.

What potentially high risk material attributes and process parameters were identified and what are the justifications? Ditto.
What process development studies, including screening, characterization, optimization, and verification (robustness) if any, were conducted and at what scale? Ditto.

What process parameters and material attributes (drug substance, excipients and in-process materials) were identified as critical? How do they impact drug product CQAs? Again: ditto.

For each potentially high risk process step (the rest of these will be answered by whoever changes any process step):

How have the risks associated with the material attributes and process parameters been reduced to an acceptable level?

How was scale dependence for each process step evaluated during pharmaceutical development?

How were the critical process parameters adjusted across lab, pilot and exhibit scale?
 
What is the Control Strategy for the drug product, including (but not limited to) the acceptable range for critical attributes of the input materials, CPPs of the manufacturing process, and CQAs of both intermediates and the finished product?

2.3.P.2.4 Container Closure System
What specific container closure system attributes are necessary to ensure drug product integrity and performance through the intended shelf life? This is critical, unless the “owner” of the product supplies all the packaging materials used. If not, then the contract manufacturer is responsible for ascertaining that the materials used are safe and protect the product. There is always a chance that someone (the product owner or the product manufacturer) will need to perform compatibility and/or stability tests with any and all materials used at that site.

What are the differences in the container closure system(s) between this product and the Reference Listed Drug (RLD)? This will need to be addressed, if the above conditions apply.

How was the container closure system qualified as suitable for use with this dosage form? Refer to the above answer.

2.3.P.2.5 Microbiological Attributes
If applicable, how are the microbiological attributes of the drug product controlled? There is a chance this may become an issue if excipients are supplied by a different vendor than supplied them for the formulation/clinical/stability studies by the originator of the ANDA. Each new vendor needs to be validated for sterility and chemical applicability for the product.

2.3.P.2.6 Compatibility
If applicable, how is the compatibility of the drug product with delivery device, additives and/or diluents addressed? This is usually covered in the original product development stage, however, if materials are introduced from new sources, there may need to be further testing involved.

What is the supportive data? Need it be mentioned that ALL notebooks must follow cGMPs?

And, don’t forget how “unhappy” the FDA is with discarded notes or continuously repeated tests?

2.3.P.3 Manufacture
Who manufactures the drug product? List each participant and facility involved in drug product manufacturing/testing activities and clearly state their function. This is where your location comes into the picture. It will make your facility liable to pre- and post-approval inspections, before and after the ANDA is approved.

What are the exhibit batch and commercial batch formulas and are they proportional? Much of this documentation will be covered by the owner of the product and submitted in the ANDA. You may be called upon for supplemental information.

If not, what are the differences and justifications? You may well need to work with the “owner” if this needs to be addressed; still, the weight of proof is on the site that makes changes, nit the site that produces the product.

2.3.P.3 Manufacture
For each process step including packaging, what is the yield and reconciliation of the exhibit batch? This will be gleaned from manufacturing records by the submitting party. Your records will be needed for inclusion.
What yield and reconciliation is proposed for commercial batches? This is usually done by the owner in consultation with your production staff.

What are the differences in batch size, equipment capacity and estimated use of capacity between the exhibit and commercial scale? Same as the question directly above.

What, if any, are the differences in equipment design and operating principle? Ditto.

What evidence (for example, theory, scale-up factors, or equations) supports the plan to scale up the process from exhibit to commercial scale? Most of this will be supplied by the “owner”/submitter with input from your production staff.

What are the in-process controls and test results for each process step? What are the differences in the in-process controls for the exhibit batch and the intended commercial batches? Usually, these will be what the “owner” has specified and your facility complies with. Unless you wish to institute (with agreement with the product owner) PAT, these will be identical with those submitted in the ANDA.

What are the justifications for any differences?

This is supplied by the submitters.

2.3.P.4 Control of Excipients
What ensures that the excipients are suitable for their intended function? This almost becomes philosophical in that most pharma companies of all sizes rarely spend much time on the processability of excipients. Much of this work is trial-and-error and “tradition,” so whatever you may have answered in the past, you may be required to provide actual data to support your position(s) now.

2.3.P.5 Control of Drug Product
What is the drug product specification? All these questions pertain to the initial formulation and production parameters of the process. If nothing else, the information can help the CMO be assured it is mirroring the approved, validated process.
Does it include all the critical drug product quality attributes?

For each test in the specification, what is the justification for the acceptance criterion?

For each test in the specification, provide a summary of the analytical method(s) and, if applicable, a summary of the validation or verification report(s).

2.3.P.6 Reference Standards and Materials
How were the reference standards used for drug product analysis certified or qualified?

2.3.P.7 Container Closure System
What container closure system(s) is proposed for packaging and storage of the drug product? This question is addressed at the early stages of formulation and stability testing. The protection needed should have been assessed, and compatibility studies carried out long before the product went to a contract manufacturer.

2.3.P.8 Stability
What is the stability specification? Again, these questions are answered by the innovator, but belong to the CMO if changes of any kind are made (by them, mostly) after the ANDA submission.

• What is the justification for acceptance criteria that differ from the drug product release specification?
• What is the proposed tentative expiration date for the drug product?
• What drug product stability studies support the proposed shelf life and storage conditions?
• What trends were observed in the stability data and do they warrant further investigation?
• What are the post-approval stability protocol and other stability commitments for the drug product?