# Presentation: 024852

## Ajaz S. Hussain, Ph.D.
Director (Act.), Office of Testing and Research
OPS, CDER, FDA

16 November 2000

- Director (Act.), Office of Testing and Research
- OPS, CDER, FDA
- 16 November 2000

- Advisory Committee for Pharmaceutical Science

**Research Update****Office of Testing and Research****Product Quality Research Institute, Inc. **

## OTR Organization

## Mission

**Advance the scientific basis of regulatory policy**
**Assure that regulatory policy and decision making are based on the best available science**
**Provide scientific and laboratory support for review, postmarketing surveillance, and compliance activities**

## OTR Program Focus

**Key Multidisciplinary Focus Areas that **
**address important areas of CDER’s mission****:**
**Nonclinical/clinical linkage**
**Product quality - improved methodology **
**Database availability and monitoring**
**Regulatory analytical support to CDER and FDA**

## Collaborations

**Product Quality Research Initiative (PQRI)**
**Advisory Committee for Pharmaceutical Science (ACPS) , Nonclinical Studies Subcommittee (NCSS)**
**Other government organizations such as  NIH, NIEHS, NCTR**
**Academia**
**Industry**

## OTR Topics

- Regulatory contributions
- Science base
- Regulatory policies and decisions
- Re-engineering efforts
- Further enhance the ability to meet the needs of the CDER
- Multidisciplinary team concept
- Strengthening linkages with review
- One example of a regulatory research project
- Excipients and risk of bio-in-equivalence

## Background:  Sorbitol

- Widely used excipient in oral liquid dosage forms
- Hexahydric alcohol related to mannose and is isomeric with mannitol
- _Low intestinal permeability_
- Metabolized in liver to fructose and glucose
- Reports of adverse reactions largely due to its action as an osmotic laxative (>20g)
- _5.48% W/V aqueous solution is iso-osmotic with serum_
- Handbook of Pharmaceutical Excipients, APhA, PhP.
- Two tablespoons (adult dose) of some commercial syrups contain upto  23g of sorbitol

## Effect on Gastro-Intestinal Transit Time (minutes)

**Adkin, et al. Br. J. Clin. Pharmac. 39: 381-387 1995**

*(sodium acid pyorphosphate)*

## Sorbitol/Mannitol: Impact on Bioavailability

- 2.3 grams of mannitol in a tablet reduced bioavailability of cimetidine (a _low permeability_ drug, per FDA’s BCS Guidance) compared to a tablet containing the same amount of sucrose
-  AUC, Cmax , and Tmax ratios of the mean values were 71%, 46%, and 167%, respectively
- Sparrow et al. J. Pharm. Sci. 84: 1405-1409, 1995)
- About 10 grams of sorbitol had no (minimal) effect on bioavailability (Cmax and AUC) of theophylline (a _high permeability_ drug)
- Fassihi et al. Int. J. Pharm. 72: 175-178, (1991)

## Study Objectives

- Published and in-house data suggests that low permeability excipients such as sorbitol (or mannitol), in amounts used in typical syrup formulations, can significantly reduce bioavailability of drugs that  also exhibit low intestinal permeability
- Bioavailability of drugs that exhibit high intestinal permeability may be less likely to be effected by these excipients
- In this study bioequivalence of a ranitidine (low permeability model) solution containing sorbitiol (5g) was assessed using as reference a ranitidine solution containing sucrose (5g)

## Formulations

- * Rapidly metabolized at/in the intestinal wall to glucose and fructose, both exhibit complete absorption

## Results: Average Profiles (n=40)

## Results: Average Profiles (n=20) 

## Bioequivalence: Average Criteria

- Note: Solution containing sucrose was used as the reference

## Individual Bioequivalence

- * S-F-I: Subject-by-formulation interaction

## Results

- On average, bioavailability of ranitidine from sorbitol solution was about 50% that of sucrose solution
- Mean Tmax for the two treatments were within 10%
- Although estimated value for Subject-by-formulation interaction was 0.15 for AUCI, it was not statistically significant (CI included 0) in this study

## Subject-by-Formulation Interaction?

- Estimate = 0.15 for AUCI

## Conclusion

- A significant risk of bioINequivalence exists between sucrose and sorbitol based syrups
- In this study, this risk was demonstrated for a low permeability model drug
- In addition to literature reports and this study results, similar trends have been observed in data available to FDA on other low permeability drugs (e.g., furosemide and atenolol)
- Literature and in-house submission data on drugs such as theophylline suggests that the risk of bioINequivalence is lower for drugs that exhibit high intestinal permeability

## Generalization of these results?

- To address this question a study was carried out with metoprolol as a model high permeability drug
- Preliminary results suggest that difference in bioavailability between sorbitol and sucrose solution is significantly less than what was observed for ranitidine

## Metoprolol Study: Preliminary Data

- Average Profiles (n=40)

## PQRIProduct Quality Research Institute

## Founding Members

**The Institute is comprised of eight founding member organizations: **
**AAPS; the Consumer Healthcare Products Association (CHPA), the Generic Pharmaceutical Industry Association (GPIA); the National Association of Pharmaceutical Manufacturers (NAPM); the National Pharmaceutical Alliance (NPA), the Parental Drug Association (PDA), the Pharmaceutical Research and Manufacturing Association (PhRMA), and the Center for Drug Evaluation and Research (CDER) of FDA. **
**AAPS is responsible for the day-to-day management of the Institute. **

## PQRI Recommendations to FDA 

**Once a project is completed by a Working Group, the outcome will be presented by the Technical Committee to the Steering Committee for dissemination to FDA and the public**
**If a vote is required on the research outcomes, FDA representatives on the Steering Committee will not vote **
**The Steering Committee will forward policy development recommendations and related research data to FDA**

## FDA

**FDA is not obligated to implement policy based on Institute information/ recommendations and may accept or reject any information/recommendations at its discretion **
**FDA has the sole statutory responsibilities for developing regulatory policy and guidance and may not delegate this responsibility **

## Safety, Efficacy and Product Quality Linkages

_**Discovery**__**	**__**Development**__**	**__**Review**_**	**_**Marketing**_

_***Pre-clinical***__***	***__***Clinical ***_
_***	***__***	***__***I, II, III          Approval         IV  AER’s***_

***Pre-formulation***
***                ***_***Formulation (Clinical)***_
***	******	******Optimization          Scale-Up      Manufacturing***
*** ***
***	******	******	******	******      ******(For Market)    Changes******	******   ***

***Safety***
***&***
***Efficacy***

***Appropriate Controls & Specifications***

*** ******Building Quality In***

**?**

**?**

## Regulatory Hypothesis Approach

**Drug Product Technical Committee**
**Ho: Adherence to CGMP’s, which include validation, and appropriately established product specifications are sufficient to assure consistent quality and performance (or equivalence) of drug products that are manufactured at different locations using alternate pharmaceutical unit operations, excipients, and container/closure systems**
**Initial Projects: IR Dosage Forms**
**Outcome: ????**

- aaps Annual Meeting

## Desired Outcome

- Reduce time and cost for implementing manufacturing changes (industry)
-  Reduce the number of CMC/Biopharm supplements
-  Reduce review load - one time review by CDER (FDA)
- Facilitate introduction of new technology and maintain the competitive edge of US industry
- Ensure that quality is ‘built-in”

- aaps Annual Meeting

## Different Perspectives

- SUPAC-IR
**CGMP’s, which include validation, and product specifications are **_**NOT**_** sufficient to assure consistent quality and performance (or equivalence) of **_**MOST**_** IR drug products that are manufactured at different locations using alternate pharmaceutical unit operations, and excipients ****(container/closure systems not covered under SUPAC-IR)**
**Why? ****Ajaz Hussain**
**Why not? ****Sid Goldstein, Arni Repta, and Stve Byrn**

- aaps Annual Meeting

## FDA Perspective: CMC

- Release testing at the time of manufacture does not provide  information that assures “shelf-life”
- Stability commitment may identify stability problems at a later time when the product is already in use by the patients, recall takes time and may be incomplete

- aaps Annual Meeting

## Major Reasons For “Recall”*

- Sub-potency
- Dissolution failures
- Super-potency
- Stability data generated did not support *expiry date*
- Failure to meet established impurity or degradant limits

**Barry Rothman, Office of Compliance, CDER, FDA, 1999*

- aaps Annual Meeting

## FDA Perspective: CMC

- A combination of long term and accelerated stability testing (*and PAS*) are currently the only means for assuring correct expiry date
- principles of accelerated stability may not be appropriate for predicting “physical” stability

- aaps Annual Meeting

## FDA Perspective: Biopharm

- In Vitro dissolution specification may not assure bioequivalence
- dissolution test is for QC only
- one point acceptance criterion
- media and hydrodynamic conditions may not reflect in vivo conditions
- IVIVC needed - tends to be “formulation specific”
- excipients may alter absorption

- aaps Annual Meeting

## Current Research Focus

- Drug Product Technical Committee
- Chairperson: Sid Goldstein
***Adherence to CGMP’s, which include validation, and appropriately established product specifications are sufficient to assure consistent quality and performance (or equivalence) of drug products that are manufactured at different locations using alternate pharmaceutical unit operations, excipients, and container/closure systems ***
***Blend uniformity***
***Manufacturing changes to IR Solid Dosage forms***
***Packaging changes***

## Rational Approaches for Powder Blend Uniformity Testing for Solid Dosage

_**Problem**_
- Current regulatory policies require demonstration of adequacy of mixing or in-process powder blend homogeneity
- Blend uniformity testing using sampling thieves is the only accepted method
- For most powder blends, blend testing for every production batch is not necessary and that unit dose sampling, using sampling thieves, can pose significant problems.
- The gap in the scientific understanding and regulatory policies are a source of continued debate and, from an industry perspective, undesirable regulatory action.
- Current policies _may be_ diverting industry and FDA time and resources to address a redundant question.

## Blend Uniformity Testing

_**Approach**_
- Identify if/when blend uniformity tests are needed to assure product quality
- Seek to enhance confidence in end product content uniformity tests to assure batch-to-batch content uniformity without the need for an in-process blend uniformity test
- Develop and validate a more effective method for testing blend uniformity when such tests are necessary

## Blend Uniformity Testing

_**Outcome**_
- Science based recommendations for development of new guidance document that will identify when and how powder blend uniformity should be tested.
- This guidance will save development time and resources and may also reduce the number of unfavorable regulatory actions (e.g., 483’s) associated with this issue.

## Current Research Focus

- Biopharmaceutics Technical Committee
- Chairperson: Elizabeth Lane
***In vitro drug release and other appropriate physico-chemical product tests can be developed to assure equivalent rate and extent of drug absorption from pharmaceutical equivalent dosage forms ***
***In Vitro Methods for Bioequivalence Assessment of IR Solid Dosage Forms (extension of BCS based biowaivers)***

## Current Research Focus

- Drug Substance Technical Committee
- Chairperson: Steve Byrn
***Adherence to CGMPs and a critical comparison of the analytical results encompassing specifications, impurity profile, and relevant physical properties will be adequate to show unchanged identity, strength, quality, purity, and potency of a drug substance in the presence of pre- and post approval changes in 1) manufacturing scale, site, equipment, controls and process; 2) route of synthesis; 3) packaging; 4) supplier(s) of drug substance***

## Current Research Focus

- Science Management Technical Committee
- Chairperson: Vacant
***The goal of this technical committee is to develop strategies that maximize the efficiency of the processes that produce an optimally performing drug product that meets public health objectives for identity, strength, quality, purity, and potency (SMTC Meeting 4 November 1998).***
***Process mapping (CMC & Biopharm.)***

## Additional Information

- WWW.PQRI.ORG