Critical in-process controls (CIPCs) include tests and measurements performed during production to monitor and, if appropriate,
adjust the manufacturing process to ensure that a drug substance or drug product's critical quality attributes are met. Deletion
of a CIPC is typically reported in a prior approval supplement. Under a PMP, the following protocol would be used to add or
tighten a CIPC or to add additional testing or parameters to the manufacturing process. These changes would be reported in
a company's annual report. For example, the report may present:
- Appropriate rationale to support the change
- Proof that the product using the new CIPCs is equivalent to the previously approved product by means of appropriate analytical
testing (e.g., dissolution profiles, batch release data)
- Results for tests listed in the drug product specification for the first three production batches following the change.
To expand the range of a CIPC, changes would be reported in a similar manner but through a CBE-30 . Table III shows acceptance
criteria that could be applied to confirm that the change has not adversely impacted the product.
Table III: Sample drug substance section of the postapproval management plan (acceptance criteria applied to confirm that
a change has not adversely impacted the product).
A PMP can be used to address packaging. The following is an example of a proposed change to the packaging material for an
API. The change could be submitted in an annual report rather than a CBE-30 if the criteria are met. The protocol could allow
for reduced data requirements by proposing the use of moisture vapor transmission rates in place of stability data.
Drug substance X will be packaged in a low-density polyethylene (LDPE) primary liner that is heat-sealed. This primary liner
will be placed inside a secondary laminated foil liner. The secondary liner will be heat-sealed. A silica gel desiccant package
for moisture absorption will be placed between the primary and the secondary liner. The sealed liners may then be placed in
an appropriate container such as a fiber drum, corrugated container, polyethylene drum, or metal drum for shipping and handling.
Table IV: API packaging material protocol.
The materials of construction of the primary packaging component LDPE liner comply with the requirements of the applicable
sections of current federal regulations for indirect food additives, 21 CFR Parts 177, 178, and 182.
The following sample protocol would be used for a change in packaging material, with the change and supporting data provided
in an annual report.
For packaging material that is in direct contact with the drug substance:
Six months of accelerated stability data for a minimum of three batches of drug substance X per the following stability protocol:
All registered acceptance criteria for the analytical properties studied must be met. A minimum of one batch of drug substance
X will be placed on stability at 25 °C and 60% relative humidity (RH) either after or concurrent with the accelerated stability
For packaging materials that are not in direct contact with the drug substance:
Option 1: Six months of accelerated stability data for a minimum of three batches of drug substance X as per the following
stability protocol: All registered acceptance criteria for the analytical properties studied must be met. A minimum of one
batch of drug substance X will be placed on stability at 25 °C and 60% RH either after or concurrent with the accelerated
Option 2: Data demonstrating that the new packaging and previous packaging design have equivalent or better moisture vapor
An effective PMP is product specific and based on sound scientific knowledge. A PMP also incorporates risk-management principles
and results with a more predictable and science-based approach to product life-cycle management. Appropriate identification
of the critical parameters and change mechanisms is of paramount importance to achieve the "desired state." The desired state,
according to FDA, is: "A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high
quality drug products without extensive regulatory oversight" (4). Overall, the PMP can reduce hurdles to continuous improvement
in pharmaceutical manufacturing, thereby opening the door to reduced costs, increased efficiency, and improved safety.
Paula S. Hudson, R.Ph., RAC*, is a manager of CMC Regulatory Affairs and Denyse D. Baker, P.E., RAC, is a principal regulatory scientist, both at Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, tel.
317.277.6730, fax 317.655.6813, email@example.com
*To whom all correspondence should be addressed.
Submitted: Apr. 30, 2008. Accepted: July 28, 2008.
1. ICH, ICH Q8 Pharmaceutical Development (Geneva, Nov. 10, 2005).
2. ICH, ICH Q9 Quality Risk Management (Geneva, Nov. 9, 2005).
3. ICH, ICH Q10 Pharmaceutical Quality System (Geneva, June 2008).
4. J. Woodcock, MD, "Pharmaceutical Quality in the 21st Century—An Integrated System Approach," presented at AAPS Workshop
on Pharmaceutical Quality Assessment—A Science- and Risk-Based CMC Approach in the 21st Century (Bethesda, MD), Oct. 5, 2005.