Controlling Microcrystalline Cellulose Variability: Understanding Process Capability and Reactive Impurities in QbD Paradigm

Though the realm of that excipient industry has metamorphosed from conventional to intricate, Microcrystalline Cellulose (MCC) has explicitly been inevitable and most sought in pharmaceutical industries for oral drug delivery system. MCC is primarily utilised as a diluent in practically all types of oral solid dosage forms, particularly tablets and capsules. The proportion of it can go high—up to 90% w/w of total formulation. Different manufacturing processes—such as direct compression, wet granulation, or roller compaction—require different grades of MCC. Additionally, specialised grades like PH 112, are more compatible with moisture-sensitive drug substances. Thus, its low variability in terms of raw material quality traits, (critical material attributes (CMAs)/Functionality related characteristics (FRCs)) helps enable consistent performance of finished product manufactured via different manufacturing processes throughout the product life cycle. 

Excipient variability control has remained unambiguously a vital aspect even in the quality by design (QbD) paradigm and as per International Conference on Harmonisation (ICH) quality visions.^1-3 The QbD paradigm envisage and emphasises science- and risk-based approaches for drug product development. Hence, identifying and controlling the CMAs/FRCs of excipient is necessary to deliver consistent drug product throughout life cycle. CMAs/FRCs are excipient properties that can eventually have impact on drug product quality traits. The same have been mentioned in Pharmacopoeias, like USP highlights loss on drying, bulk density and particle size distribution whereas Ph.Eur. states particle size distribution and powder flow. Apart from that, non-compendial CMA/FRC can also be of importance like dark particle count or abnormal visual particles, which also affects the product performance in terms of appearance/description. These CMAs/FRCs probably will be monitored by regulatory bodies. 

Process Capability Analysis at Three-Sigma to Demonstrate Consistent and Reproducible CMAs/FRCs 

Process capability analysis assesses whether a process is capable of producing output that meets your desired quality traits. A capable process produces products that meet your desired specifications and is directly related to consistency of batch to batch. Complying to a three-sigma technology can help to de-risk the use of excipients like MCC, in line with QbD and ICH Q8/9 expectations, and ensure consistency in meeting FRCs (EP) and/or CMAs (USP) like bulk density, tapped density, particle size distribution, loss on drying, dark particle counts, etc., which are pertinent to tablets and capsules formulation manufacturing. Moreover, the consistency and reproducibility of these CMAs/FRCs also benefits continuous manufacturing. The process capability indices Cp, CPU, CPL and Cpk can be computed for potential within capability and Pp, PPU, PPL and Ppk can be computed for overall capability, respectively. Cp and Pp measures whether the process spread is narrower than the specification width and is indicative of process precision in terms of variability. Cpk and Ppk measure both the centering of the process as well as the spread of the process relative to the specification width. It also considers both location and variability.^4,5 

The output of the n number of batches with respect to each CMAs/FRCs results can be subjected to process capability analysis to demonstrate a three-sigma compliance. All the indices value above 1.33 for each CMAs/FRCs indicates that the process passes the capability analysis at 3 σ standard deviation process spread and the process is capable of producing batches consistently that conform to specifications. The sample size should be sufficient to evaluate statistically. The greater the sample size, the better the evaluation. Analysis can be continuous, and can be updated in annual product quality review. 

Reactive Impurities in Microcrystalline Cellulose 

Excipient with reactive impurities can affect drug product stability issues, leading to inferior product performance, decrease in potency, and/or formation of potentially toxic degradants. An excipient’s reactive impurity levels can differ between lots and vendors. Screening excipients for these impurities and a thorough understanding of their potential interaction with Active Pharmaceutical Ingredients (API) during early formulation development ensures robust drug product development. A proper control strategy should be defined for the identified reactive impurities to ensure robust product performance throughout the product life cycle. As an example, an in-house specification of reactive impurities can be set as a control with pre-defined limits, even though non-compendial. It will also ensure consistent raw material input. A validated analytical method can be adopted to test the reactive impurities. 

Here are some key reactive impurities pertinent to MCC: 

Nitrite and Nitrate Levels 

Nitrosamines are classified as probable human carcinogens. The FDA as well as EMEA guidelines recommends drug product manufacturer to assess the risk of it being present in drug products and carry out suitable testing by validated method, if a risk is identified.^6,7 Pharmaceutical industries should have an effective control strategy to prevent or restrict the presence of these impurities in the drug product. The risk evaluation also applies to the excipients used in the manufacturing of finished dosage forms. MCC is one of the inevitable diluents used in manufacturing oral solid dosage forms, and its proportion can go up to huge percentage in the formulations. 

Nitrite and nitrate are major reactive impurities found in MCC.^8,9 Although the precise sources of these trace impurities have not been investigated, they may originate from process, water, processing steps, etc. As known nitrites are common, nitrosating impurities that may lead to formation of N-nitroso API impurities in the drug product may be during manufacturing process and/ or shelf life of drug product. These nitrosoamine impurities are critical for formulation containing APIs like Ranitidine, Sartans, Metformin, etc. 

Since MCC makes up a sizable fraction of many formulations, one should emphasise the excipient’s role and any reactive impurities in it apart from drug substances. The situation becomes even more critical when an excipient becomes a major part of the formulation, like MCC. Therefore, control it to the negligible levels, and keep a specification of it in MCC itself whenever risk is high and/or based on the nature of the formulation. A proper control strategy of it should be defined like specifications for consistent raw material attributes/input throughout the product life cycle. 

Peroxides Level 

Peroxides are one of the other key reactive impurities found in MCC.8 They may be introduced into it during manufacturing process, incorporation of bleaching agent, etc. Avoid using a bleaching agent during the manufacturing process, because they can cause significant increases in hydrogen peroxide levels in MCC, which can severely affect molecules prone to undergo oxidation. 

The current pharmaceutical industries emphasise peroxide control in excipients like povidone, crospovidone, etc., which typically goes into tablets and capsules in an approximate 2-8% w/w. However, focus should be shifted for peroxide control in the excipient like MCC, which can go up to 90% w/w in the formulation as a diluent. 

To detect hydrogen peroxide levels in MCC, employ a validated analytical method like UV or HPLC. A proper control strategy for it should be defined for consistent raw material attributes/input like specifications throughout the product life cycle.

Xylose Content/Aldehyde Content 

The manufacturing of MCC employs controlled hydrolysis of α- cellulose from wood pulp with dilute mineral acids. The hemicellulose undergoes hydrolysis when heated with acids to yield xylose, and other five-carbon sugars, which may undergo dehydration to form furfuraldehyde. For MCC, there is a relationship between highly reactive furfural, and measured absolute content of xylose.¹⁰ Depending on the formulation type, residual aldehydes or furfural may impact the drug product stability. A proper control strategy of it should be defined for consistent raw material attributes/input wherever critical to API/formulations. 

Abnormal Visual Particles/Dark Particles 

Technically unavoidable particles or dark particles is one of the major concerns for MCC—even though it doesn’t impact safety. However, the presence of these particles can affect appearance/description of tablets. This is especially true with uncoated tablets. The dark particles should be controlled not only through sourcing of good wood pulp, but also with good manufacturing process to keep it at a minimum. It can also be a part of specification for release COA of MCC. This will help drug product manufactures to put as a control strategy, and ensure consistent drug product quality traits. Figure 1 portrays the typical CMAs/FRCs, and key reactive impurities for MCC. Table 1 depicts the typical control strategy for MCC PH 112 raw material during formulation development, and commercialization. It should be only considered as reference, and representation purpose. Specification/control strategy may change from vendor to vendor, and for different formulation types. 

Conclusion 

Pharmaceutical companies are embracing QbD to better understand how raw material variability impacts the drug product performance. The scientific roots established by excipient manufacturers enables consistent CMAs/FRCs as well as control of reactive impurities for MCC, thereby benefitting success and growth of any pharmaceutical or nutraceutical industry by getting timely approval as well as circumventing any hiccups during commercial and product life cycle. 

References 

1. ICH Harmonized Tripartite Guideline (2009) Pharmaceutical development Q8 (R2), August 2009. 

2. ICH Harmonized Tripartite Guideline. Quality risk management Q9, November 2005. 

3. ICH Harmonized Tripartite Guideline. Pharmaceutical Quality System Q10. June 2008. 

4. Rudisill F, Litteral LA (2008) Capability ratios: Comparison and interpretation of short-term and overall indices. Int J Qual Stand 2(1), Paper 3, 67–86. 

5. Kane VE (1986) Process capability indices. J Qual Technol 18:41–52. 

6. Control of Nitrosamine Impurities in Human Drugs, Guidance for Industry, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), February 2021. 

7. Nitrosamine impurities in human medicinal products, Assessment report, Committee for Medicinal Products for Human Use (CHMP), 25 June, 2020. 

8. Yongmei Wu, Jaquan Levons, Ajit S. Narang, Krishnaswamy Raghavan, and Venkatramana M. Rao. Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug– Excipient Incompatibility. AAPS PharmSciTech, Vol. 12, No. 4, December 2011. 

9. KellyZhang, Jackson D.Pellett, Ajit S.Narang, Y. JohnWang, Yonghua Taylor Zhang. Reactive impurities in large and small molecule pharmaceutical excipients – A review. Trends in Analytical Chemistry, Volume 101, April 2018, Pages 34-42. 

10. Excipia; Xylose and furfural in MCC. Variability in excipients – Xylose in Microcrystalline cellulose. Available at https://excipia.eu/ wp-content/uploads/2018/03/Excipia-Xylose-and-furfural-in-MCC. pdf. Last accessed on August 17, 2022. Email: info@chemfields.com; chintan.vora@chemfields.com