Best practices for the development, scale-up, and post-approval change control of IR and MR dosage forms in the current quality-by-design paradigm.

In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro-in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.

Passive transdermal systems whitepaper incorporating current chemistry, manufacturing and controls (CMC) development principles.

In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration's Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro-in vivo correlation considerations for transdermal systems.

Quality by design in formulation and process development for a freeze-dried, small molecule parenteral product: a case study.

A case study has been developed to illustrate one way of incorporating a Quality by Design approach into formulation and process development for a small molecule, freeze-dried parenteral product. Sodium ethacrynate was chosen as the model compound. Principal degradation products of sodium ethacrynate result from hydrolysis of the unsaturated ketone in aqueous solution, and dimer formation from a Diels-Alder condensation in the freeze-dried solid state. When the drug crystallizes in a frozen solution, the eutectic melting temperature is above -5°C. Crystallization in the frozen system is affected by pH in the range of pH 6-8 and buffer concentration in the range of 5-50 mM, where higher pH and lower buffer concentration favor crystallization. Physical state of the drug is critical to solid state stability, given the relative instability of amorphous drug. Stability was shown to vary considerably over the ranges of pH and buffer concentration examined, and vial-to-vial variability in degree of crystallinity is a potential concern. The formulation design space was constructed in terms of pH and drug concentration, and assuming a constant 5 mM concentration of buffer. The process design space is constructed to take into account limitations on the process imposed by the product and by equipment capability.

A QbD case study: Bayesian prediction of lyophilization cycle parameters.

As stipulated by ICH Q8 R2 (1), prediction of critical process parameters based on process modeling is a part of enhanced, quality by design approach to product development. In this work, we discuss a Bayesian model for the prediction of primary drying phase duration. The model is based on the premise that resistance to dry layer mass transfer is product specific, and is a function of nucleation temperature. The predicted duration of primary drying was experimentally verified on the lab scale lyophilizer. It is suggested that the model be used during scale-up activities in order to minimize trial and error and reduce costs associated with expensive large scale experiments. The proposed approach extends the work of Searles et al. (2) by adding a Bayesian treatment to primary drying modeling.

An experimental and theoretical investigation on torrefaction of a large wet wood particle.

A competitive kinetic scheme representing primary and secondary reactions is proposed for torrefaction of large wet wood particles. Drying and diffusive, convective and radiative mode of heat transfer is considered including particle shrinking during torrefaction. The model prediction compares well with the experimental results of both mass fraction residue and temperature profiles for biomass particles. The effect of temperature, residence time and particle size on torrefaction of cylindrical wood particles is investigated through model simulations. For large biomass particles heat transfer is identified as one of the controlling factor for torrefaction. The optimum torrefaction temperature, residence time and particle size are identified. The model may thus be integrated with CFD analysis to estimate the performance of an existing torrefier for a given feedstock. The performance analysis may also provide useful insight for design and development of an efficient torrefier.

Quantified gene expression levels for phase I/II metabolizing enzyme and estrogen receptor levels in benign prostate from cohorts designated as high-risk (UK) versus low-risk (India) for adenocarcinoma at this organ site: a preliminary study.

Risk of clinically significant prostate adenocarcinoma (CaP) varies worldwide, although there is a uniform prevalence of latent disease. A hormone-responsive tissue, the prostate possesses the metabolizing capacity to biotransform a variety of environmental procarcinogens or endogenous hormones. Whether such metabolizing capacity or estrogen receptor (ER) status underlies these demographic differences in susceptibility to CaP remains unclear. With appropriate ethical permission, verified-benign tissues were obtained following transurethral resection of the prostate from a high-risk region (n = 12 UK-resident Caucasians) and a typically low-risk region (n = 14 India-resident Asians). Quantitative gene expression analysis was employed for cytochrome P450 (CYP)1B1, N-acetyltransferase (NAT)1, NAT2, catechol-O-methyl transferase (COMT), sulfotransferase (SULT)1A1, ERalpha, ERbeta and aromatase (CYP19A1). To quantify the presence or absence of CYP1B1, ERalpha or ERbeta, and to identify their in situ localization, immunohistochemistry was carried out. The two cohorts had reasonably well-matched serum levels of prostate-specific antigen or hormones. Expression levels for the candidate genes investigated were similar. However, clear differences in protein levels for CYP1B1 and ERbeta were noted. Staining for CYP1B1 tended to be nuclear-associated in the basal glandular epithelial cells, and in UK-resident Caucasian tissues was present at a higher (P = 0.006) level compared with that from India-resident Asians. In contrast, a higher level of positive ERbeta staining was noted in prostates from India-resident Asians. These study findings point to differences in metabolizing capacity and ER status in benign prostate tissues that might modulate susceptibility to the emergence of clinically significant CaP in demographically distinct populations.